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Suganya S, Ashok BS, Ajith TA. A Recent Update on the Role of Estrogen and Progesterone in Alzheimer's Disease. Cell Biochem Funct 2024; 42:e70025. [PMID: 39663597 DOI: 10.1002/cbf.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/23/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024]
Abstract
Alzheimer's disease (AD), one of the most prevalent neurodegenerative disease responsible for 60%-80% dementia cases globally. The disease is more prevalent among elder females. Female reproductive hormones are found to be essential for cellular activities in brain. The physiological role of neurotrophins and sex hormones in hippocampal region during neurogenesis and neuron differentiation was studied as well. In addition to triggering cellular pathways, estrogen and progesterone carry out a number of biological processes that lead to neuroprotection. They might have an impact on learning and memory. One of estrogen's modest antioxidant properties is its direct scavenging of free radicals. The neurotrophic effect of estrogen and progesterone can be explained by their ability to rise the expression of the brain-derived neurotrophic factor (BDNF) mRNA. Additionally, they have the ability to degrade beta-amyloid and stop inflammation, apoptotic neuronal cell death, and tau protein phosphorylation. To enhance their neuroprotective action, various cross-talking pathways in cells that are mediated by estrogen, progesterone, and BDNF receptors. This include signaling by mitogen-activated protein kinase/extracellular regulated kinase, phosphatidylinositol 3-kinase/protein kinase B, and phospholipase/protein kinase C. Clinical research to establish the significance of these substances are fragmented, despite publications claiming a lower prevalence of AD when medication is started before menopause. This review article emphasizes an update on the role of estrogen, and progesterone in AD.
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Affiliation(s)
- S Suganya
- Department of Biochemistry, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India
| | - Ben Sundra Ashok
- Department of Biochemistry, Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India
| | - Thekkuttuparambil Ananthanarayanan Ajith
- Department of Biochemistry, Amala Institute of Medical Sciences, Thrissur, Kerala, India
- Amala Integrated Medical Research Department, Amala Institute of Medical Sciences, Thrissur, Kerala, India
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2
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Fotakopoulos G, Gatos C, Georgakopoulou VE, Christodoulidis G, Kagkouras I, Trakas N, Foroglou N. Exploring the Role of Sigma Receptors in the Treatment of Cancer: A Narrative Review. Cureus 2024; 16:e70946. [PMID: 39502961 PMCID: PMC11537387 DOI: 10.7759/cureus.70946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2024] [Indexed: 11/08/2024] Open
Abstract
This study investigated the association of sigma receptors (SRs) and their selective ligands (because the molecular characteristics of the same SRs, particularly sigma-2 receptor {S2R}, are not completely clear) in carcinogenesis, their potential use as antitumor agents, and their great utility in tumor imaging. The ion channels and transporters enhance the cell's ability to adapt to the metabolic conditions encountered in the tumor tissue. The high expression of SRs in the proliferating cells compared with those at rest indicates that this is a significant clinical biomarker for determining the proliferative status of solid tumors using functional PET imaging techniques. The association of SRs in the pathophysiology of cancer cells is a result of the high concentration of S1R and S2R binding sites observed in various tumor cell lines and tissues. It would also be remarkable to determine if SRs are involved in metastasis and other metastatic cell behaviors such as adhesion, secretion, motility, and penetration. An absolute challenge for research in this field is to develop an integrated model that describes the molecular mechanisms of sigma receptors, incorporating their known biological and pathophysiological roles.
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Affiliation(s)
| | - Charalabos Gatos
- Neurosurgery, General University Hospital of Larissa, Larissa, GRC
| | | | | | | | | | - Nikolaos Foroglou
- Neurosurgery, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, GRC
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Alluri SR, Zheng M, Holden D, Zhang Y, Zhang L, Felchner Z, Li S, Ropchan J, Carson R, Jia H, Huang Y. Evaluation of a First PET Tracer Suitable for Imaging the Sigma-2 Receptor in the Brain of Nonhuman Primates. Mol Pharm 2024; 21:194-200. [PMID: 38013422 DOI: 10.1021/acs.molpharmaceut.3c00750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
The sigma-2 receptor (σ2R), recently identified as transmembrane protein 97, is expressed in many cell types and mediates important functions in both the peripheral and central nervous systems. Over the years, σ2R has emerged as a potential therapeutic target for cancer and neurological disorders such as Alzheimer's disease (AD). The currently available σ2R radiotracers have been developed primarily for cancer imaging with limited brain uptake. Here, we report the evaluation of the first brain penetrant 18F-labeled radiotracer suitable for positron emission tomography (PET) imaging of σ2R in nonhuman primate brain.
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Affiliation(s)
| | - MingQiang Zheng
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Daniel Holden
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Ying Zhang
- College of Chemistry, Beijing Normal University, Beijing 100875, China
| | - Li Zhang
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Zachary Felchner
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Songye Li
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Jim Ropchan
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Richard Carson
- PET Center, Yale University, New Haven, Connecticut 06520, United States
| | - Hongmei Jia
- College of Chemistry, Beijing Normal University, Beijing 100875, China
| | - Yiyun Huang
- PET Center, Yale University, New Haven, Connecticut 06520, United States
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Thitilertdecha P, Brimson JM. CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer's Disease Treatment: A Systematic Review of Available Clinical Data. J Alzheimers Dis 2024; 101:S115-S128. [PMID: 39422939 DOI: 10.3233/jad-230994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Background Alzheimer's disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials. Objective The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD. Methods Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript. Results CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome. Conclusions CT1812 safely works to displace Aβ however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing.
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Affiliation(s)
- Premrutai Thitilertdecha
- Siriraj Research Group in Immunobiology and Therapeutic Sciences, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - James Michael Brimson
- Research Unit for Innovation and International Affairs, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
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Tobeh NS, Bruce KD. Emerging Alzheimer's disease therapeutics: promising insights from lipid metabolism and microglia-focused interventions. Front Aging Neurosci 2023; 15:1259012. [PMID: 38020773 PMCID: PMC10630922 DOI: 10.3389/fnagi.2023.1259012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/03/2023] [Indexed: 12/01/2023] Open
Abstract
More than 55 million people suffer from dementia, with this number projected to double every 20 years. In the United States, 1 in 3 aged individuals dies from Alzheimer's disease (AD) or another type of dementia and AD kills more individuals than breast cancer and prostate cancer combined. AD is a complex and multifactorial disease involving amyloid plaque and neurofibrillary tangle formation, glial cell dysfunction, and lipid droplet accumulation (among other pathologies), ultimately leading to neurodegeneration and neuronal death. Unfortunately, the current FDA-approved therapeutics do not reverse nor halt AD. While recently approved amyloid-targeting antibodies can slow AD progression to improve outcomes for some patients, they are associated with adverse side effects, may have a narrow therapeutic window, and are expensive. In this review, we evaluate current and emerging AD therapeutics in preclinical and clinical development and provide insight into emerging strategies that target brain lipid metabolism and microglial function - an approach that may synergistically target multiple mechanisms that drive AD neuropathogenesis. Overall, we evaluate whether these disease-modifying emerging therapeutics hold promise as interventions that may be able to reverse or halt AD progression.
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Affiliation(s)
- Nour S Tobeh
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kimberley D Bruce
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Nguyen NT, Jaramillo-Martinez V, Mathew M, Suresh VV, Sivaprakasam S, Bhutia YD, Ganapathy V. Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis. Int J Mol Sci 2023; 24:14672. [PMID: 37834119 PMCID: PMC10572259 DOI: 10.3390/ijms241914672] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein-protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.
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Affiliation(s)
| | | | | | | | | | | | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (N.T.N.); (V.J.-M.); (M.M.); (V.V.S.); (S.S.); (Y.D.B.)
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Christmann U, Díaz JL, Pascual R, Bordas M, Álvarez I, Monroy X, Porras M, Yeste S, Reinoso RF, Merlos M, Vela JM, Almansa C. Discovery of WLB-89462, a New Drug-like and Highly Selective σ 2 Receptor Ligand with Neuroprotective Properties. J Med Chem 2023; 66:12499-12519. [PMID: 37607512 DOI: 10.1021/acs.jmedchem.3c01060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σ2R) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 (20c) with good σ2R affinity (Ki = 13 nM) and high selectivity vs both the σ1R (Ki = 1777 nM) and a general panel of 180 targets. It represents one of the first σ2R ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents). Compound 20c shows neuroprotective activity in vitro and improves short-term memory impairment induced by hippocampal injection of amyloid β peptide in rats. Together with the promising effects in the chronic models where 20c is currently being evaluated, these results pave the way toward its clinical development as a neuroprotective agent.
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Affiliation(s)
- Ute Christmann
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - José Luis Díaz
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Rosalia Pascual
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Magda Bordas
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Inés Álvarez
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Xavier Monroy
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Mónica Porras
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Sandra Yeste
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Raquel F Reinoso
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Manuel Merlos
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - José Miguel Vela
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
| | - Carmen Almansa
- Welab Barcelona, Parc Científic Barcelona, C/Baldiri Reixac 4-8,08028 Barcelona, Spain
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Cao T, Wang L, Jiao S, Chen H, Lin C, Zhang B, Cai H. The Involvement of PGRMC1 Signaling in Cognitive Impairment Induced by Long-Term Clozapine Treatment in Rats. Neuropsychobiology 2023; 82:346-358. [PMID: 37673050 DOI: 10.1159/000533148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 07/09/2023] [Indexed: 09/08/2023]
Abstract
INTRODUCTION Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. METHODS In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. RESULTS Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. CONCLUSION PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.
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Affiliation(s)
- Ting Cao
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - LiWei Wang
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - ShiMeng Jiao
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hui Chen
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - ChenQuan Lin
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - BiKui Zhang
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
| | - HuaLin Cai
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
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Asady B, Sampels V, Romano JD, Levitskaya J, Lige B, Khare P, Le A, Coppens I. Function and regulation of a steroidogenic CYP450 enzyme in the mitochondrion of Toxoplasma gondii. PLoS Pathog 2023; 19:e1011566. [PMID: 37651449 PMCID: PMC10499268 DOI: 10.1371/journal.ppat.1011566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 09/13/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023] Open
Abstract
As an obligate intracellular parasite, Toxoplasma gondii must import essential nutrients from the host cell into the parasitophorous vacuole. We previously reported that the parasite scavenges cholesterol from host endocytic organelles for incorporation into membranes and storage as cholesteryl esters in lipid droplets. In this study, we have investigated whether Toxoplasma utilizes cholesterol as a precursor for the synthesis of metabolites, such as steroids. In mammalian cells, steroidogenesis occurs in mitochondria and involves membrane-bound type I cytochrome P450 oxidases that are activated through interaction with heme-binding proteins containing a cytochrome b5 domain, such as members of the membrane-associated progesterone receptor (MAPR) family. Our LC-MS targeted lipidomics detect selective classes of hormone steroids in Toxoplasma, with a predominance for anti-inflammatory hydroxypregnenolone species, deoxycorticosterone and dehydroepiandrosterone. The genome of Toxoplasma contains homologs encoding a single type I CYP450 enzyme (we named TgCYP450mt) and a single MAPR (we named TgMAPR). We showed that TgMAPR is a hemoprotein with conserved residues in a heme-binding cytochrome b5 domain. Both TgCYP450 and TgMAPR localize to the mitochondrion and show interactions in in situ proximity ligation assays. Genetic ablation of cyp450mt is not tolerated by Toxoplasma; we therefore engineered a conditional knockout strain and showed that iΔTgCYP450mt parasites exhibit growth impairment in cultured cells. Parasite strains deficient for mapr could be generated; however, ΔTgMAPR parasites suffer from poor global fitness, loss of plasma membrane integrity, aberrant mitochondrial cristae, and an abnormally long S-phase in their cell cycle. Compared to wild-type parasites, iΔTgCYP450mt and ΔTgMAPR lost virulence in mice and metabolomics studies reveal that both mutants have reduced levels of steroids. These observations point to a steroidogenic pathway operational in the mitochondrion of a protozoan that involves an evolutionary conserved TgCYP450mt enzyme and its binding partner TgMAPR.
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Affiliation(s)
- Beejan Asady
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Vera Sampels
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Julia D. Romano
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Jelena Levitskaya
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Bao Lige
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Pratik Khare
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Anne Le
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Isabelle Coppens
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
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Wang T, Jia H. The Sigma Receptors in Alzheimer's Disease: New Potential Targets for Diagnosis and Therapy. Int J Mol Sci 2023; 24:12025. [PMID: 37569401 PMCID: PMC10418732 DOI: 10.3390/ijms241512025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 08/13/2023] Open
Abstract
Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy.
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Affiliation(s)
- Tao Wang
- Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;
- Department of Nuclear Medicine, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Hongmei Jia
- Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;
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11
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Wang L, Chen Q, Ma R, Zhang B, Yang P, Cao T, Jiao S, Chen H, Lin C, Cai H. Insight into mitochondrial dysfunction mediated by clozapine-induced inhibition of PGRMC1 in PC12 cells. Toxicology 2023; 491:153515. [PMID: 37087062 DOI: 10.1016/j.tox.2023.153515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/11/2023] [Accepted: 04/19/2023] [Indexed: 04/24/2023]
Abstract
Clozapine is usually considered as the last resort for treatment-resistant schizophrenia (TRS). However, it shows limited efficacy in cognition improvement. Moreover, the metabolic side effects induced by clozapine can aggravate cognitive impairment, which is closely related to its neurotoxicity. Nevertheless, the mechanisms underlying clozapine's neurotoxicity remain largely elusive. In this study, PC12 cells were simultaneously treated with different concentrations (0μM, 10μM, 20μM, 40μM and 80μM) of clozapine and AG205 which functions as a blocking reagent of progesterone receptor membrane component 1 (PGRMC1). In addition, we examined the effect of PGRMC1 in clozapine-induced neurotoxicity through overexpressing or downregulating PGRMC1. Molecular docking and surface plasmon resonance (SPR) analysis indicated that clozapine and AG205 inhibited the binding of endogenous progesterone to PGRMC1. The results showed that high concentration of clozapine and AG205 induced a significant increase in cytotoxicity, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse, all of which were worsened as concentration increases, while overexpression of PGRMC1 reverted the above toxic effect of clozapine on PC12 cells. Furthermore, clozapine and AG205 also downregulated the expression of PGRMC1, glucagon-like peptide-1 receptor (GLP-1R) and mitofusin2 (Mfn2). Interestingly, overexpression of PGRMC1 could revert these effects. Our data suggest that overexpression of PGRMC1 in PC12 cells prevents and restores clozapine-induced oxidative and mitochondrial damage. We propose PGRMC1 activation as a promising therapeutic strategy for clozapine-induced neurotoxicity to facilitate the relief of neuronal damage.
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Affiliation(s)
- Liwei Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Qian Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Rui Ma
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Ping Yang
- Department of Psychiatry, Hunan Brain Hospital, 427# Furong Road, Changsha, Hunan 410000, China
| | - Ting Cao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Shimeng Jiao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Hui Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Chenquan Lin
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China
| | - Hualin Cai
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.
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12
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Thejer BM, Infantino V, Santarsiero A, Pappalardo I, Abatematteo FS, Teakel S, Van Oosterum A, Mach RH, Denora N, Lee BC, Resta N, Bagnulo R, Niso M, Contino M, Montsch B, Heffeter P, Abate C, Cahill MA. Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97. Int J Mol Sci 2023; 24:ijms24076381. [PMID: 37047353 PMCID: PMC10093951 DOI: 10.3390/ijms24076381] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/22/2023] [Accepted: 03/22/2023] [Indexed: 03/31/2023] Open
Abstract
Sigma-2 receptor (S2R) is a S2R ligand-binding site historically associated with reportedly 21.5 kDa proteins that have been linked to several diseases, such as cancer, Alzheimer’s disease, and schizophrenia. The S2R is highly expressed in various tumors, where it correlates with the proliferative status of the malignant cells. Recently, S2R was reported to be the transmembrane protein TMEM97. Prior to that, we had been investigating the translocator protein (TSPO) as a potential 21.5 kDa S2R candidate protein with reported heme and sterol associations. Here, we investigate the contributions of TMEM97 and TSPO to S2R activity in MCF7 breast adenocarcinoma and MIA PaCa-2 (MP) pancreatic carcinoma cells. Additionally, the role of the reported S2R-interacting partner PGRMC1 was also elucidated. Proximity ligation assays and co-immunoprecipitation show a functional association between S2R and TSPO. Moreover, a close physical colocalization of TMEM97 and TSPO was found in MP cells. In MCF7 cells, co-immunoprecipitation only occurred with TMEM97 but not with PGRMC1, which was further confirmed by confocal microscopy experiments. Treatment with the TMEM97 ligand 20-(S)-hydroxycholesterol reduced co-immunoprecipitation of both TMEM97 and PGRMC1 in immune pellets of immunoprecipitated TSPO in MP cells. To the best of our knowledge, this is the first suggestion of a (functional) interaction between TSPO and TMEM97 that can be affected by S2R ligands.
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Affiliation(s)
- Bashar M. Thejer
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia
- Research and Development Department, The Ministry of Higher Education and Scientific Research, Baghdad 10065, Iraq
| | - Vittoria Infantino
- Department of Science, University of Basilicata, Viale dell’Ateneo lucano 10, 85100 Potenza, Italy
| | - Anna Santarsiero
- Department of Science, University of Basilicata, Viale dell’Ateneo lucano 10, 85100 Potenza, Italy
| | - Ilaria Pappalardo
- Department of Science, University of Basilicata, Viale dell’Ateneo lucano 10, 85100 Potenza, Italy
| | - Francesca S. Abatematteo
- Department of Pharmacy-Drug Sciences, University of Bari ‘ALDO MORO’, Via Orabona 4, 70125 Bari, Italy
| | - Sarah Teakel
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia
| | - Ashleigh Van Oosterum
- Life Sciences and Health, Faculty of Science, Charles Sturt University, Wagga Wagga, NSW 2650, Australia
- School of Medicine and Psychology, Australian National University, Florey Building, 54 Mills Road, Acton, ACT 2601, Australia
| | - Robert H. Mach
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nunzio Denora
- Department of Pharmacy-Drug Sciences, University of Bari ‘ALDO MORO’, Via Orabona 4, 70125 Bari, Italy
| | - Byung Chul Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Republic of Korea
- Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon 16229, Republic of Korea
| | - Nicoletta Resta
- Dipartimento di Medicina di Precisione e Rigenerativa e Area Jonica (DIMePRe-J), Università degli Studi di Bari ‘ALDO MORO’, Piazza Giulio Cesare, 70124 Bari, Italy
| | - Rosanna Bagnulo
- Dipartimento di Medicina di Precisione e Rigenerativa e Area Jonica (DIMePRe-J), Università degli Studi di Bari ‘ALDO MORO’, Piazza Giulio Cesare, 70124 Bari, Italy
| | - Mauro Niso
- Department of Pharmacy-Drug Sciences, University of Bari ‘ALDO MORO’, Via Orabona 4, 70125 Bari, Italy
| | - Marialessandra Contino
- Department of Pharmacy-Drug Sciences, University of Bari ‘ALDO MORO’, Via Orabona 4, 70125 Bari, Italy
| | - Bianca Montsch
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Petra Heffeter
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Carmen Abate
- Department of Pharmacy-Drug Sciences, University of Bari ‘ALDO MORO’, Via Orabona 4, 70125 Bari, Italy
- Consiglio Nazionale delle Ricerche (CNR), Istituto di Cristallografia, Via Amendola, 70125 Bari, Italy
- Correspondence:
| | - Michael A. Cahill
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia
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13
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Lizama BN, Kahle J, Catalano SM, Caggiano AO, Grundman M, Hamby ME. Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases. Int J Mol Sci 2023; 24:ijms24076251. [PMID: 37047224 PMCID: PMC10093856 DOI: 10.3390/ijms24076251] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/18/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration.
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Affiliation(s)
| | | | | | | | - Michael Grundman
- Global R&D Partners, LLC., San Diego, CA 92130, USA
- Department of Neurosciences, University of California, San Diego, CA 92093, USA
| | - Mary E. Hamby
- Cognition Therapeutics, Inc., Pittsburgh, PA 15203, USA
- Correspondence:
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14
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Abatematteo FS, Majellaro M, Montsch B, Prieto-Díaz R, Niso M, Contino M, Stefanachi A, Riganti C, Mangiatordi GF, Delre P, Heffeter P, Sotelo E, Abate C. Development of Fluorescent 4-[4-(3 H-Spiro[isobenzofuran-1,4'-piperidin]-1'-yl)butyl]indolyl Derivatives as High-Affinity Probes to Enable the Study of σ Receptors via Fluorescence-Based Techniques. J Med Chem 2023; 66:3798-3817. [PMID: 36919956 PMCID: PMC10041534 DOI: 10.1021/acs.jmedchem.2c01227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Sigma (σ) receptor subtypes, σ1 and σ2, are targets of wide pharmaceutical interest. The σ2 receptor holds promise for the development of diagnostics and therapeutics against cancer and Alzheimer's disease. Nevertheless, little is known about the mechanisms activated by the σ2 receptor. To contribute to the exploitation of its therapeutic potential, we developed novel specific fluorescent ligands. Indole derivatives bearing the N-butyl-3H-spiro[isobenzofuran-1,4'-piperidine] portion were functionalized with fluorescent tags. Nanomolar-affinity fluorescent σ ligands, spanning from green to red to near-infrared emission, were obtained. Compounds 19 (σ pan affinity) and 29 (σ2 selective), which displayed the best compromise between pharmacodynamic and photophysical properties, were investigated in flow cytometry, confocal, and live cell microscopy, demonstrating their specificity for the σ2 receptor. To the best of our knowledge, these are the first red-emitting fluorescent σ2 ligands, validated as powerful tools for the study of σ2 receptors via fluorescence-based techniques.
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Affiliation(s)
| | - Maria Majellaro
- Centro Singular Investigación Quimica Biologica e Materiales Moleculares (CIQUS), Departamento de Quimica Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Bianca Montsch
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Rubén Prieto-Díaz
- Centro Singular Investigación Quimica Biologica e Materiales Moleculares (CIQUS), Departamento de Quimica Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Mauro Niso
- Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, 79125 Bari, Italy
| | | | - Angela Stefanachi
- Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, 79125 Bari, Italy
| | - Chiara Riganti
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
| | | | - Pietro Delre
- Consiglio Nazionale delle Ricerche (CNR), Istituto di Cristallografia, Via Amendola, 70126 Bari, Italy
| | - Petra Heffeter
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Eddy Sotelo
- Centro Singular Investigación Quimica Biologica e Materiales Moleculares (CIQUS), Departamento de Quimica Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Carmen Abate
- Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4, 79125 Bari, Italy
- Consiglio Nazionale delle Ricerche (CNR), Istituto di Cristallografia, Via Amendola, 70126 Bari, Italy
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15
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Gao RD, Taylor M, McInnis T, Chen Z, Gori SS, LaPorte HM, Siegler MA, Neisewander JL, Mach RH, Singh M, Slusher BS, Rais R, Luedtke RR, Tsukamoto T. Synthesis and Pharmacological Characterization of a Difluorinated Analogue of Reduced Haloperidol as a Sigma-1 Receptor Ligand. ACS Chem Neurosci 2023; 14:947-957. [PMID: 36780706 PMCID: PMC11622112 DOI: 10.1021/acschemneuro.2c00791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Reduced haloperidol (1) was previously reported to act as a potent sigma-1 receptor (S1R) ligand with substantially lower affinity to the dopamine D2 receptor (D2R) compared to haloperidol. It was also found to facilitate brain-derived neurotrophic factor (BDNF) secretion from astrocytic glial cell lines in a sigma-1 receptor (S1R)-dependent manner. Although an increase in BDNF secretion may have beneficial effects in some neurological conditions, the therapeutic utility of reduced haloperidol (1) is limited because it can be oxidized back to haloperidol in the body, a potent dopamine D2 receptor antagonist associated with well-documented adverse effects. A difluorinated analogue of reduced haloperidol, (±)-4-(4-chlorophenyl)-1-(3,3-difluoro-4-(4-fluorophenyl)-4-hydroxybutyl)piperidin-4-ol (2), was synthesized in an attempt to minimize the oxidation. Compound (±)-2 was found to exhibit high affinity to S1R and facilitate BDNF release from mouse brain astrocytes. It was also confirmed that compound 2 cannot be oxidized back to the corresponding haloperidol analogue in liver microsomes. Furthermore, compound 2 was distributed to the brain following intraperitoneal administration in mice and reversed the learning deficits in active avoidance tasks. These findings suggest that compound 2 could serve as a promising S1R ligand with therapeutic potential for the treatment of cognitive impairments.
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Affiliation(s)
- Run-Duo Gao
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Michelle Taylor
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
| | - Tamara McInnis
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
| | - Zhenglan Chen
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
| | - Sadakatali S Gori
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Heather M LaPorte
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, United States
| | - Maxime A Siegler
- Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, United States
| | - Janet L Neisewander
- School of Life Sciences, Arizona State University, Tempe, Arizona 85287, United States
| | - Robert H Mach
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Meharvan Singh
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, United States
| | - Barbara S Slusher
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Rana Rais
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Robert R Luedtke
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, United States
| | - Takashi Tsukamoto
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
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16
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Aickareth J, Hawwar M, Sanchez N, Gnanasekaran R, Zhang J. Membrane Progesterone Receptors (mPRs/PAQRs) Are Going beyond Its Initial Definitions. MEMBRANES 2023; 13:membranes13030260. [PMID: 36984647 PMCID: PMC10056622 DOI: 10.3390/membranes13030260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/10/2023] [Accepted: 02/19/2023] [Indexed: 05/13/2023]
Abstract
Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.
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17
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Roy J, Kyani A, Hanafi M, Xu Y, Takyi-Williams J, Sun D, Osman EEA, Neamati N. Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer. J Med Chem 2023; 66:1990-2019. [PMID: 36692906 DOI: 10.1021/acs.jmedchem.2c01769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Sigma 2 receptor (σ2R) is overexpressed in select cancers and is regarded as a biomarker for tumor proliferation. σ2R ligands are emerging as promising theranostics for cancer and neurodegenerative diseases. Herein, we describe the design and synthesis of a series of novel quinolyl pyrazinamides as selective and potent σ2R ligands that show sub-micromolar potency in pancreatic cancer cell lines. Compounds 14 (JR1-157) and 17 (JR2-298) bind σ2R with Ki of 47 and 10 nM, respectively. Importantly, compound 14 has an oral bioavailability of 60% and shows significant in vivo efficacy without obvious toxicity in a syngeneic model of pancreatic cancer. The cytotoxicity of the quinolyl pyrazinamides significantly enhanced in the presence of copper and diminished in the presence of the copper-chelator tetrathiomolybdate. In conclusion, compound 14 is water-soluble, metabolically stable, orally active, and increases the expression of the autophagy marker LC3B and warrants further development for the treatment of pancreatic cancer.
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Affiliation(s)
- Joyeeta Roy
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Armita Kyani
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Maha Hanafi
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Yibin Xu
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - John Takyi-Williams
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.,Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Duxin Sun
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.,Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Essam Eldin A Osman
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.,Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Nouri Neamati
- Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
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18
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Ribarič S. Detecting Early Cognitive Decline in Alzheimer's Disease with Brain Synaptic Structural and Functional Evaluation. Biomedicines 2023; 11:355. [PMID: 36830892 PMCID: PMC9952956 DOI: 10.3390/biomedicines11020355] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
Early cognitive decline in patients with Alzheimer's (AD) is associated with quantifiable structural and functional connectivity changes in the brain. AD dysregulation of Aβ and tau metabolism progressively disrupt normal synaptic function, leading to loss of synapses, decreased hippocampal synaptic density and early hippocampal atrophy. Advances in brain imaging techniques in living patients have enabled the transition from clinical signs and symptoms-based AD diagnosis to biomarkers-based diagnosis, with functional brain imaging techniques, quantitative EEG, and body fluids sampling. The hippocampus has a central role in semantic and episodic memory processing. This cognitive function is critically dependent on normal intrahippocampal connections and normal hippocampal functional connectivity with many cortical regions, including the perirhinal and the entorhinal cortex, parahippocampal cortex, association regions in the temporal and parietal lobes, and prefrontal cortex. Therefore, decreased hippocampal synaptic density is reflected in the altered functional connectivity of intrinsic brain networks (aka large-scale networks), including the parietal memory, default mode, and salience networks. This narrative review discusses recent critical issues related to detecting AD-associated early cognitive decline with brain synaptic structural and functional markers in high-risk or neuropsychologically diagnosed patients with subjective cognitive impairment or mild cognitive impairment.
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Affiliation(s)
- Samo Ribarič
- Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia
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19
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Weng CC, Riad A, Lieberman BP, Xu K, Peng X, Mikitsh JL, Mach RH. Characterization of Sigma-2 Receptor-Specific Binding Sites Using [ 3H]DTG and [ 125I]RHM-4. Pharmaceuticals (Basel) 2022; 15:ph15121564. [PMID: 36559015 PMCID: PMC9784403 DOI: 10.3390/ph15121564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/30/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
The sigma-2 receptor/transmembrane protein 97 (σ2R/TMRM97) is a promising biomarker of tumor proliferation and a target for cancer therapy. [3H]DTG has been used to evaluate σ2R/TMEM97 binding affinity in compound development studies. However, [3H]DTG has equal and moderate binding affinities to both sigma 1 receptor (σ1R) and σ2R/TMEM97. Furthermore, co-administration with the σ1R masking compound (+)-pentazocine may cause bias in σ2R/TMEM97 binding affinity screening experiments. We have developed a radioiodinated ligand, [125I]RHM-4, which has high affinity and selectivity for σ2R/TMEM97 versus σ1R. In this study, a head-to-head comparison between [3H]DTG and [125I]RHM-4 on the binding affinity and their effectiveness in σ2R/TMEM97 compound screening studies was performed. The goal of these studies was to determine if this radioiodinated ligand is a suitable replacement for [3H]DTG for screening new σ2R/TMEM97 compounds. Furthermore, to delineate the binding properties of [125I]RHM-4 to the σ2R/TMEM97, the structure of RHM-4 was split into two fragments. This resulted in the identification of two binding regions in the σ2R, the "DTG" binding site, which is responsible for binding to the σ2R/TMEM97, and the secondary binding site, which is responsible for high affinity and selectivity for the σ2R/TMEM97 versus the σ1R. The results of this study indicate that [125I]RHM-4 is an improved radioligand for in vitro binding studies of the σ2R/TMEM97 versus [3H]DTG.
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Affiliation(s)
- Chi-Chang Weng
- HARC and Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan 333, Taiwan
- Department of Nuclear Medicine and Center for Advanced Molecular Imaging and Translation, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aladdin Riad
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Brian P. Lieberman
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kuiying Xu
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xin Peng
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - John L. Mikitsh
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert H. Mach
- Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Correspondence: ; Tel.: +1-215-746-8233
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20
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Wendler A, Wehling M. Many or too many progesterone membrane receptors? Clinical implications. Trends Endocrinol Metab 2022; 33:850-868. [PMID: 36384863 DOI: 10.1016/j.tem.2022.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 10/07/2022] [Accepted: 10/12/2022] [Indexed: 11/15/2022]
Abstract
Several receptors for nongenomically initiated actions of progesterone (P4) exist, namely membrane-associated P4 receptors (MAPRs), membrane progestin receptors (mPRs), receptors for neurosteroids [GABAA receptor (GABAAR), NMDA receptor, sigma-1 and -2 receptors (S1R/S2R)], the classical genomic P4 receptor (PGR), and α/β hydrolase domain-containing protein 2 (ABHD2). Two drugs related to this field have been approved: brexanolone (Zulresso™) for the treatment of postpartum depression, and ganaxolone (Ztalmy™) for the treatment of CDKL5 deficiency disorder. Both are derivatives of P4 and target the GABAAR. Several other indications are in clinical testing. CT1812 (Elayta™) is also being tested for the treatment of Alzheimer's disease (AD) in Phase 2 clinical trials, targeting the P4 receptor membrane component 1 (PGRMC1)/S2R complex. In this Review, we highlight emerging knowledge on the mechanisms of nongenomically initiated actions of P4 and its derivatives.
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Affiliation(s)
- Alexandra Wendler
- Clinical Pharmacology Mannheim, Faculty of Medicine Mannheim, Ruprecht-Karls-University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
| | - Martin Wehling
- Clinical Pharmacology Mannheim, Faculty of Medicine Mannheim, Ruprecht-Karls-University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany.
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21
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Martin SF. Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience. Acc Chem Res 2022; 55:2397-2408. [PMID: 35960884 DOI: 10.1021/acs.accounts.1c00773] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Scientific excursions into the unknown are often characterized by unanticipated twists and turns that may lead in directions that never could have been predicted. Decisions made during the course of these explorations determine what we discover. This Account chronicles one such journey that began with a challenge encountered during the synthesis of a natural product and then unfolded over more than 30 years to focus on unmet needs in neuroscience. Specifically, while developing a concise approach to tetrahydroalstonine, a heteroyohimboid alkaloid having α-adrenergic activity, we faced the predicament of assembling a key intermediate. Solving this problem resulted in the serendipitous discovery of the vinylogous Mannich reaction and a productive program wherein we used this powerful construction as a key step in the syntheses of numerous alkaloids. However, we also realized that lessons learned from the synthesis of tetrahydroalstonine could be generalized to invent a new strategy for preparing diverse collections of substituted nitrogen heterocycles that could be screened against biological targets. The approach featured the combination of several reactants in a multicomponent assembly process to give a functionalized intermediate that could be elaborated by various ring-forming reactions to give heterocyclic scaffolds that could be further diversified. Screening these compound sets against a broad range of biological targets revealed some intriguing hits, but none of them led to a productive collaboration in translational research. Notwithstanding this setback, we screened curated members of our collections against proteins in the central nervous system and discovered some substituted B-norbenzomorphans that were selective for the enigmatic sigma-2 receptor (σ2R), an understudied protein that had been primarily associated with cancer. With scant knowledge of its role in neuroscience, we posited that small molecules that bind to σ2R might be neuroprotective, thus launching a new venture. In parallel investigations we prepared analogues of the initial hits, explored their effects in animal models of neurodegenerative and neurological conditions, and identified σ2R as transmembrane protein 97 (TMEM97). After first establishing the neuroprotective effects of several σ2R/TMEM97 ligands in a transgenic Caenorhabditis elegans model of neurodegeneration, we showed that one of these has procognitive effects and reduces levels of proinflammatory cytokines in a transgenic mouse model of Alzheimer's disease. We then identified a closely related σ2R/TMEM97 ligand that mitigates hippocampal-dependent memory deficits, prevents axon degeneration, and protects neurons and oligodendrocytes after traumatic brain injury. In a recent study, this compound was shown to protect retinal ganglion cells from retinal ischemia/reperfusion injury. In other collaborative investigations, we have shown that related, but structurally distinct, σ2R/TMEM97 ligands alleviate neuropathic pain, while a σ2R/TMEM97 ligand representing yet another chemotype reduces impairments associated with alcohol withdrawal. More recently, we have shown that σ2R/TMEM97 ligands enhance survival of cortical neurons in a neuronal model of Huntington's disease. Translational and mechanistic studies in these and other areas are in progress. Solving a problem we faced in natural product synthesis thus served as an unexpected gateway to discoveries that could lead to entirely new approaches to treat neurodegenerative and neurological conditions by targeting σ2R/TMEM97, a protein that has never been associated with these afflictions.
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Affiliation(s)
- Stephen F Martin
- Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States
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22
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Fallica AN, Ciaffaglione V, Modica MN, Pittalà V, Salerno L, Amata E, Marrazzo A, Romeo G, Intagliata S. Structure-activity relationships of mixed σ1R/σ2R ligands with antiproliferative and anticancer effects. Bioorg Med Chem 2022; 73:117032. [DOI: 10.1016/j.bmc.2022.117032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 11/27/2022]
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23
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Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands. Int J Mol Sci 2022; 23:ijms23158259. [PMID: 35897835 PMCID: PMC9332756 DOI: 10.3390/ijms23158259] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 01/27/2023] Open
Abstract
A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo[2.2.1]heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein.
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24
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Kim HY, Lee JY, Hsieh CJ, Riad A, Izzo NJ, Catalano SM, Graham TJA, Mach RH. Screening of σ 2 Receptor Ligands and In Vivo Evaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ 2 Receptor Brain PET Tracer. J Med Chem 2022; 65:6261-6272. [PMID: 35404616 DOI: 10.1021/acs.jmedchem.2c00191] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Ki for σ1 = 48.4 ± 7.7 nM, and Ki for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (Ki for σ1 = 108 ± 35 nM, and Ki for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.
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Affiliation(s)
- Ho Young Kim
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Ji Youn Lee
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Chia-Ju Hsieh
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Aladdin Riad
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Nicholas J Izzo
- Cognition Therapeutics Inc., Pittsburgh, Pennsylvania 15203-5118, United States
| | - Susan M Catalano
- Cognition Therapeutics Inc., Pittsburgh, Pennsylvania 15203-5118, United States
| | - Thomas J A Graham
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Robert H Mach
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
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25
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Abatematteo FS, Mosier PD, Niso M, Brunetti L, Berardi F, Loiodice F, Contino M, Delprat B, Maurice T, Laghezza A, Abate C. Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ 1) receptor ligands with potent anti-amnesic effect. Eur J Med Chem 2022; 228:114038. [PMID: 34902734 DOI: 10.1016/j.ejmech.2021.114038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/24/2021] [Accepted: 12/01/2021] [Indexed: 12/21/2022]
Abstract
The sigma-1 (σ1) receptor plays a significant role in many normal physiological functions and pathological disease states, and as such represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines based on the lead compound 1-[ω-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1a) in which the degree of methylation at the carbon atoms alpha to the piperidine nitrogen was systematically varied. The affinity at σ1 and σ2 receptors and at Δ8-Δ7 sterol isomerase (SI) ranged from subnanomolar to micromolar Ki values. While the highest-affinity was displayed at the σ1, the increase of the degree of methylation in the piperidine ring progressively decreased the affinity. The subnanomolar affinity 1a and 1-[ω-(4-methoxyphenoxy)ethyl]-4-methylpiperidine (1b) displayed potent anti-amnesic effects associated with σ1 receptor agonism, in two memory tests. Automated receptor-small-molecule ligand docking provided a molecular structure-based rationale for the agonistic effects of 1a and 1b. Overall, the class of the phenoxyalkylpiperidines holds potential for the development of high affinity σ1 receptor agonists, and compound 1a, that appears as the best in class (exceeding by far the activity of the reference compound PRE-084) deserves further investigation.
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Affiliation(s)
- Francesca S Abatematteo
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy
| | - Philip D Mosier
- Department of Biopharmaceutical Sciences, School of Pharmacy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Mauro Niso
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy
| | - Leonardo Brunetti
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy
| | - Francesco Berardi
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy
| | - Fulvio Loiodice
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy
| | - Marialessandra Contino
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy
| | - Benjamin Delprat
- MMDN, University of Montpellier, EPHE, INSERM, Montpellier, France
| | - Tangui Maurice
- MMDN, University of Montpellier, EPHE, INSERM, Montpellier, France
| | - Antonio Laghezza
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy.
| | - Carmen Abate
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, ALDO MORO, Via Orabona, 4, I-70125, Bari, Italy.
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26
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Solairaja S, Ramalingam S, Dunna NR, Venkatabalasubramanian S. Progesterone Receptor Membrane Component 1 and Its Accomplice: Emerging Therapeutic Targets in Lung Cancer. Endocr Metab Immune Disord Drug Targets 2021; 22:601-611. [PMID: 34847852 DOI: 10.2174/1871530321666211130145542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/13/2021] [Accepted: 10/28/2021] [Indexed: 12/24/2022]
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is a trans-membrane evolutionarily conserved protein with a cytochrome b5 like heme/steroid binding domain. PGRMC1 clinical levels are strongly suggested to correlate with poor patient survival and lung cancer prognosis. PGRMC1 has been reported to possess pleiotropic functions, such as participating in cellular and membrane trafficking, steroid hormone signaling, cholesterol metabolism and steroidogenesis, glycolysis and mitochondrial energy metabolism, heme transport and homeostasis, neuronal movement and synaptic function, autophagy, anti-apoptosis, stem cell survival and the list is still expanding. PGRMC1 mediates its pleiotropic functions through its ability to interact with multiple binding partners, such as epidermal growth factor receptor (EGFR), sterol regulatory element binding protein cleavage activating protein (SCAP), insulin induced gene-1 protein (Insig-1), heme binding proteins (hepcidin, ferrochelatase and cyp450 members), plasminogen activator inhibitor 1 RNA binding protein (PAIR-BP1). In this review, we provide a comprehensive overview of PGRMC1 and its associated pleiotropic functions that are indispensable for lung cancer promotion and progression, suggesting it as a prospective therapeutic target for intervention. Notably, we have compiled and reported various preclinical studies wherein prospective agonists and antagonists had been tested against PGRMC1 expressing cancer cell lines, suggesting it as a prospective therapeutic target for cancer intervention.
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Affiliation(s)
- Solaipriya Solairaja
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur Campus, Tamil Nadu, Chennai-603203. India
| | - Satish Ramalingam
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur Campus, Tamil Nadu, Chennai-603203. India
| | - Nageswara Rao Dunna
- Cancer Genomics Laboratory, Department of Biotechnology, School of Chemical and Biotechnology, SASTRA - Deemed University, Thanjavur 613 401. India
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27
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Alamri MA, Alamri MA. Adamantane-derived scaffolds targeting the sigma-2 receptor; an in vitro and in silico study. Saudi Pharm J 2021; 29:1166-1172. [PMID: 34703370 PMCID: PMC8523332 DOI: 10.1016/j.jsps.2021.08.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/23/2021] [Indexed: 11/23/2022] Open
Abstract
Novel adamantane-based compounds were synthesized and assessed as potential sigma-2 receptor ligands. Molecular docking and 50 ns molecular dynamic simulation were carried out to determine the binding modes, mechanism of interaction, and stability of these compounds within the active site of the sigma-2 receptor. In addition, the ADME-T properties have been explored. The cytotoxicity in cancer cell lines that express sigma-2 receptors was also examined. In addition, the in silico and cytotoxicity data for the new compounds were compared to a reference sigma-2 receptor ligand with high receptor-binding affinity and selectivity. The data suggests that the new compounds interact with the sigma-2 receptor in a comparable manner to the reference compound, and that adamantane can be used as a scaffold to synthesize sigma-2 receptor ligands with useful functional groups that can be used to conjugate moieties for tumor-imaging or cytotoxic cargo delivery.
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Affiliation(s)
- Mohammed A. Alamri
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia
| | - Mubarak A. Alamri
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia
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28
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Rishton GM, Look GC, Ni ZJ, Zhang J, Wang Y, Huang Y, Wu X, Izzo NJ, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, Catalano SM. Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease. ACS Med Chem Lett 2021; 12:1389-1395. [PMID: 34531947 DOI: 10.1021/acsmedchemlett.1c00048] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 08/03/2021] [Indexed: 02/08/2023] Open
Abstract
An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aβ oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer's disease.
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Affiliation(s)
- Gilbert M. Rishton
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Gary C. Look
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Zhi-Jie Ni
- Acme Bioscience, Inc., 3941 East Bayshore Road, Palo Alto, California 94303, United States
| | - Jason Zhang
- Acme Bioscience, Inc., 3941 East Bayshore Road, Palo Alto, California 94303, United States
| | - Yingcai Wang
- Acme Bioscience, Inc., 3941 East Bayshore Road, Palo Alto, California 94303, United States
| | - Yaodong Huang
- Acme Bioscience, Inc., 3941 East Bayshore Road, Palo Alto, California 94303, United States
| | - Xiaodong Wu
- Acme Bioscience, Inc., 3941 East Bayshore Road, Palo Alto, California 94303, United States
| | - Nicholas J. Izzo
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Kelsie M LaBarbera
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Colleen S. Limegrover
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Courtney Rehak
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Raymond Yurko
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
| | - Susan M. Catalano
- Cognition Therapeutics, 2403 Sidney Street, Suite 261, Pittsburgh, Pennsylvania 15203, United States
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29
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QSAR-Based Computational Approaches to Accelerate the Discovery of Sigma-2 Receptor (S2R) Ligands as Therapeutic Drugs. Molecules 2021; 26:molecules26175270. [PMID: 34500703 PMCID: PMC8434483 DOI: 10.3390/molecules26175270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/05/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022] Open
Abstract
S2R overexpression is associated with various forms of cancer as well as both neuropsychiatric disorders (e.g., schizophrenia) and neurodegenerative diseases (Alzheimer’s disease: AD). In the present study, three ligand-based methods (QSAR modeling, pharmacophore mapping, and shape-based screening) were implemented to select putative S2R ligands from the DrugBank library comprising 2000+ entries. Four separate optimization algorithms (i.e., stepwise regression, Lasso, genetic algorithm (GA), and a customized extension of GA called GreedGene) were adapted to select descriptors for the QSAR models. The subsequent biological evaluation of selected compounds revealed that three FDA-approved drugs for unrelated therapeutic indications exhibited sub-1 uM binding affinity for S2R. In particular, the antidepressant drug nefazodone elicited a S2R binding affinity Ki = 140 nM. A total of 159 unique S2R ligands were retrieved from 16 publications for model building, validation, and testing. To our best knowledge, the present report represents the first case to develop comprehensive QSAR models sourced by pooling and curating a large assemblage of structurally diverse S2R ligands, which should prove useful for identifying new drug leads and predicting their S2R binding affinity prior to the resource-demanding tasks of chemical synthesis and biological evaluation.
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30
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Current development of sigma-2 receptor radioligands as potential tumor imaging agents. Bioorg Chem 2021; 115:105163. [PMID: 34289426 DOI: 10.1016/j.bioorg.2021.105163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 07/05/2021] [Accepted: 07/08/2021] [Indexed: 12/24/2022]
Abstract
Sigma receptors are transmembrane proteins with two different subtypes: σ1 and σ2. Because of its overexpression in tumors, the σ2 receptor (σ2R) is a well-known biomarker for cancer cells. A large number of small-molecule ligands for the σ2Rs have been identified and tested for imaging the proliferative status of tumors using single photon emission computed tomography (SPECT) and positron emission tomography (PET). These small molecules include derivatives of bicyclic amines, indoles, cyclohexylpiperazines and tetrahydroisoquinolines. This review discusses various aspects of small molecule ligands, such as chemical composition, labeling strategy, affinity for σ2Rs, and in vitro/in vivo investigations. The recent studies described here could be useful for the development of σ2R radioligands as potential tumor imaging agents.
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31
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Abatematteo FS, Niso M, Lacivita E, Abate C. σ 2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach. Molecules 2021; 26:3743. [PMID: 34205334 PMCID: PMC8235595 DOI: 10.3390/molecules26123743] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 11/19/2022] Open
Abstract
Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases.
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Affiliation(s)
| | | | | | - Carmen Abate
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Via Orabona 4, 70125 Bari, Italy; (F.S.A.); (M.N.); (E.L.)
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32
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Fallica AN, Pittalà V, Modica MN, Salerno L, Romeo G, Marrazzo A, Helal MA, Intagliata S. Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective. J Med Chem 2021; 64:7926-7962. [PMID: 34076441 PMCID: PMC8279423 DOI: 10.1021/acs.jmedchem.0c02265] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
![]()
Since their discovery
as distinct receptor proteins, the specific
physiopathological role of sigma receptors (σRs) has been deeply
investigated. It has been reported that these proteins, classified
into two subtypes indicated as σ1 and σ2, might play a pivotal role in cancer growth, cell proliferation,
and tumor aggressiveness. As a result, the development of selective
σR ligands with potential antitumor properties attracted significant
attention as an emerging theme in cancer research. This perspective
deals with the recent advances of σR ligands as novel cytotoxic
agents, covering articles published between 2010 and 2020. An up-to-date
description of the medicinal chemistry of selective σ1R and σ2R ligands with antiproliferative and cytotoxic
activities has been provided, including major pharmacophore models
and comprehensive structure–activity relationships for each
main class of σR ligands.
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Affiliation(s)
- Antonino N Fallica
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Valeria Pittalà
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Maria N Modica
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Loredana Salerno
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Giuseppe Romeo
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Agostino Marrazzo
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Mohamed A Helal
- University of Science and Technology, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, sixth of October, Giza 12578, Egypt.,Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Sebastiano Intagliata
- Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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33
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Romeo G, Bonanno F, Wilson LL, Arena E, Modica MN, Pittalà V, Salerno L, Prezzavento O, McLaughlin JP, Intagliata S. Development of New Benzylpiperazine Derivatives as σ 1 Receptor Ligands with in Vivo Antinociceptive and Anti-Allodynic Effects. ACS Chem Neurosci 2021; 12:2003-2012. [PMID: 34019387 PMCID: PMC8291485 DOI: 10.1021/acschemneuro.1c00106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/10/2021] [Indexed: 12/22/2022] Open
Abstract
σ-1 receptors (σ1R) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σ1R and selectivity over the σ-2 receptor (σ2R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ1R receptor affinity (Ki σ1 = 1.6 nM) among the series with a significant improvement of the σ1R selectivity (Ki σ2/Ki σ1= 886) compared to the lead compound 8 (Ki σ2/Ki σ1= 432). Compound 15 was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3-60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound 15 demonstrated no significant effects in a rotarod assay, suggesting that this σ1R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ1R antagonists as potential therapeutics for chronic pain.
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Affiliation(s)
- Giuseppe Romeo
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Federica Bonanno
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Lisa L. Wilson
- Department
of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Emanuela Arena
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Maria N. Modica
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Valeria Pittalà
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Loredana Salerno
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Orazio Prezzavento
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
| | - Jay P. McLaughlin
- Department
of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Sebastiano Intagliata
- Department
of Drug and Health Sciences, University
of Catania, viale A. Doria 6, 95125 Catania, Italy
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Ma WH, Chen AF, Xie XY, Huang YS. Sigma ligands as potent inhibitors of Aβ and AβOs in neurons and promising therapeutic agents of Alzheimer's disease. Neuropharmacology 2021; 190:108342. [PMID: 33045243 DOI: 10.1016/j.neuropharm.2020.108342] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/14/2020] [Accepted: 10/01/2020] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disease and characterized by dementia, memory decline, loss of learning and cognitive disorder. The main pathological features of AD are the deposition of amyloid plaques and the formation of neurofibrillary tangles (NFTs) in the brain. The current anti-AD drugs have shown unsatisfactory therapeutic results. Due to the complications and unclear pathogenesis, AD is still irreversible and incurable. Among several hypotheses proposed by the academic community, the amyloid cascade is widely recognized by scholars and supported by a large amount of evidences. However, controversy over pathogenic factors has also been ongoing. Increasing evidence has shown that amyloid-β (Aβ) and especially amyloid-β oligomers (AβOs) are highly neurotoxic and pathogenic agents that damage neurons, mediate various receptors in the downstream pathways, and ultimately lead to learning and cognitive dysfunction. However, efforts in developing inhibitors of Aβ or amyloid-β precursor protein (APP) have all failed to yield good clinical results. More recently, it has been demonstrated that sigma receptors, including sigma-1 and sigma-2 subtypes, may play critical roles in the regulation of binding and metabolism of AβOs in neuron cells and the pathophysiology of AD. Thus, sigma receptor ligands are being recognized as promising therapeutic agents for treating or ameliorating AD. This article will review the pathophysiology of AD and highlight the sigma ligands that display the capability of preventing or even reversing Aβ- and AβOs-induced neurotoxicity and blocking the signal transduction caused by AβOs.
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Affiliation(s)
- Wen-Hui Ma
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China; Dongguan Key Laboratory for Drug Design & Formulation, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Ai-Fang Chen
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China; Dongguan Key Laboratory for Drug Design & Formulation, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Xiao-Yang Xie
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China; Dongguan Key Laboratory for Drug Design & Formulation, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Yun-Sheng Huang
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China; Dongguan Key Laboratory for Drug Design & Formulation, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
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Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ 2 Receptor Ligand. Int J Mol Sci 2021; 22:ijms22115447. [PMID: 34064122 PMCID: PMC8196714 DOI: 10.3390/ijms22115447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/18/2021] [Accepted: 05/18/2021] [Indexed: 01/14/2023] Open
Abstract
The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.
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Faheem, Karan Kumar B, Venkata Gowri Chandra Sekhar K, Chander S, Kunjiappan S, Murugesan S. 1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design. Expert Opin Drug Discov 2021; 16:1119-1147. [PMID: 33908322 DOI: 10.1080/17460441.2021.1916464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Cancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design.Areas covered: This review article addresses the potential of THIQ as anticancer agents. Various medicinal chemistry strategies employed for the design and development of THIQ analogs as inhibitors or modulators of relevant anticancer targets have been discussed in detail. Moreover, the common strategies employed for the synthesis of the core scaffold are also highlighted.Expert opinion: Evidently, THIQs have tremendous potential in anticancer drug design. Some of these analogs exhibited potent activity against various cancer molecular targets. However, there are some drawbacks, such as selectivity that need addressing. The synthetic ease for constructing the core scaffold complimented with its reactivity makes it ideal for further structure-activity relationship studies. For these reasons, THIQ is a privileged scaffold for the design and development of novel anticancer agents.
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Affiliation(s)
- Faheem
- Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani, India
| | - Banoth Karan Kumar
- Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani, India
| | | | - Subhash Chander
- Amity Institute of Phytomedicine and Phytochemistry, Amity University Uttar Pradesh, Noida, India
| | - Selvaraj Kunjiappan
- Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, India
| | - Sankaranarayanan Murugesan
- Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani, India
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Díaz JL, Cuevas F, Oliva AI, Font D, Sarmentero MÁ, Álvarez-Bercedo P, López-Valbuena JM, Pericàs MA, Enrech R, Montero A, Yeste S, Vidal-Torres A, Álvarez I, Pérez P, Cendán CM, Cobos EJ, Vela JM, Almansa C. Tricyclic Triazoles as σ 1 Receptor Antagonists for Treating Pain. J Med Chem 2021; 64:5157-5170. [PMID: 33826322 DOI: 10.1021/acs.jmedchem.1c00244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.
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Affiliation(s)
- José Luis Díaz
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Félix Cuevas
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
| | - Ana I Oliva
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
| | - Daniel Font
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
| | - M Ángeles Sarmentero
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
| | - Paula Álvarez-Bercedo
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
| | - José M López-Valbuena
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
| | - Miquel A Pericàs
- The Barcelona Institute of Science and Technology, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
- Departament de Química Inorgànica i Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain
| | - Raquel Enrech
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Ana Montero
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Sandra Yeste
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Alba Vidal-Torres
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Inés Álvarez
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Pilar Pérez
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Cruz Miguel Cendán
- Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain
| | - Enrique J Cobos
- Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain
- Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain
| | - José Miguel Vela
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
| | - Carmen Almansa
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals S.A., Carrer Baldiri Reixac, 4-8. Parc Científic de Barcelona, 08028 Barcelona, Spain
- WELAB, Parc Científic Barcelona, C/Baldiri Reixac 4-8, 08028 Barcelona, Spain
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Atif F, Yousuf S, Espinosa-Garcia C, Stein DG. Progesterone Modulates Mitochondrial Functions in Human Glioblastoma Cells. Mol Neurobiol 2021; 58:3805-3816. [PMID: 33847913 DOI: 10.1007/s12035-021-02382-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/31/2021] [Indexed: 11/25/2022]
Abstract
A substantial literature supports the notion that cancer is a metabolic disease. Mitochondria are sexually dimorphic, and progesterone (P4) plays a key regulatory role in mitochondrial functions. We investigated the effect of P4 on mitochondrial functions in three human glioblastoma multiforme (GBM) cell lines. In dose-response and time-response studies, GBM cells were exposed to different concentrations of P4 followed by mitochondrial stress-testing with a Seahorse analyzer. Data were analyzed for oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and spare respiratory capacity (SRC) to determine the effects of P4 exposure on mitochondrial respiration and rate of glycolysis. We also examined the effect of P4 on mitochondrial superoxide radical generation by confocal microscopy. As early as 1h post-P4 exposure, we found a substantial dose-dependent inhibitory effect of P4 on OCR, ECAR, and SRC in all GBM cell lines. P4 treatment altered the levels of basal respiration, maximum respiration, nonmitochondrial oxygen consumption, ATP production, and proton leak. P4 given at 80-μM concentration showed the maximum inhibitory effect compared to controls. Live imaging data showed an 11-22% increase in superoxide radical generation in all three GBM cell lines following 6h exposure to a high concentration of P4. Our data show that high-dose P4 exerts an inhibitory effect on both mitochondrial respiration and glycolysis in GBM cells. These effects would lead to decreased tumor size and rate of growth, representing a potential treatment to control the spread of GBM.
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Affiliation(s)
- Fahim Atif
- Brain Research Laboratory, Department of Emergency Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Room 655A, Atlanta, GA, 30322, USA.
| | - Seema Yousuf
- Brain Research Laboratory, Department of Emergency Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Room 655A, Atlanta, GA, 30322, USA
| | - Claudia Espinosa-Garcia
- Brain Research Laboratory, Department of Emergency Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Room 655A, Atlanta, GA, 30322, USA
| | - Donald G Stein
- Brain Research Laboratory, Department of Emergency Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Room 655A, Atlanta, GA, 30322, USA
- Neuroscience and Behavioral Biology Program, Emory College of Arts and Sciences, Atlanta, GA, 30322, USA
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39
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Bergkemper M, Schepmann D, Wünsch B. Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers. ChemMedChem 2021; 16:1184-1197. [PMID: 33332704 PMCID: PMC8048568 DOI: 10.1002/cmdc.202000861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/14/2020] [Indexed: 12/11/2022]
Abstract
With the aim to develop new σ2 receptor ligands, spirocyclic piperidines or cyclohexanamines with 2-benzopyran and 2-benzofuran scaffolds were connected to the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety by variable linkers. In addition to flexible alkyl chains, linkers containing an amide as functional group were synthesized. The 2-benzopyran and 2-benzofuran scaffold of the spirocyclic compounds were synthesized from 2-bromobenzaldehyde. The amide linkers were constructed by acylation of amines with chloroacetyl chloride and subsequent nucleophilic substitution, the alkyl linkers were obtained by LiAlH4 reduction of the corresponding amides. For the development of σ2 receptor ligands, the spirocyclic 2-benzopyran scaffold is more favorable than the ring-contracted 2-benzofuran system. Compounds bearing an alkyl chain as linker generally show higher σ affinity than acyl linkers containing an amide as functional group. A higher σ1 affinity for the cis-configured cyclohexanamines than for the trans-configured derivatives was found. The highest σ2 affinity was observed for cis-configured spiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine connected to the tetrahydroisoquinoline system by an ethylene spacer (cis-31, Ki (σ2 )=200 nM; the highest σ1 affinity was recorded for the corresponding 2-benzofuran derivative with a CH2 C=O linker (cis-29, Ki (σ1 )=129 nM).
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Affiliation(s)
- Melanie Bergkemper
- Institut für Pharmazeutische und Medizinische ChemieWestfälische Wilhelms-Universität MünsterCorrensstr. 4848149MünsterGermany
| | - Dirk Schepmann
- Institut für Pharmazeutische und Medizinische ChemieWestfälische Wilhelms-Universität MünsterCorrensstr. 4848149MünsterGermany
| | - Bernhard Wünsch
- Institut für Pharmazeutische und Medizinische ChemieWestfälische Wilhelms-Universität MünsterCorrensstr. 4848149MünsterGermany
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40
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Maurice T. Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders. Expert Opin Drug Discov 2021; 16:373-389. [PMID: 33070647 DOI: 10.1080/17460441.2021.1838483] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/14/2020] [Indexed: 12/19/2022]
Abstract
Introduction: The sigma-1 receptor (S1R) is attracting much attention for disease-modifying therapies in neurodegenerative diseases. It is a conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca2+ transfer and ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in diseases such as Alzheimer, Parkinson, Huntington or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases.Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the bi-phasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials.Expert opinion: S1R agonists modulate inter-organelles communication altered in neurodegenerative diseases and activate intracellular survival pathways. Research will continue growing in the future. The particular cellular nature of this chaperone protein must be better understood to facilitate the clinical developement of promising molecules.
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Affiliation(s)
- Tangui Maurice
- MMDN, Univ Montpellier, EPHE, INSERM, UMR_S1198, Montpellier, France
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41
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Mir RH, Mohi-ud-din R, Wani TU, Dar MO, Shah AJ, Lone B, Pooja C, Masoodi MH. Indole: A Privileged Heterocyclic Moiety in the Management of Cancer. CURR ORG CHEM 2021. [DOI: 10.2174/1385272825666210208142108] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Heterocyclic are a class of compounds that are intricately entwined into life processes.
Almost more than 90% of marketed drugs carry heterocycles. Synthetic chemistry, in
turn, allocates a cornucopia of heterocycles. Among the heterocycles, indole, a bicyclic structure
consisting of a six-membered benzene ring fused to a five-membered pyrrole ring with
numerous pharmacophores that generate a library of various lead molecules. Due to its profound
pharmacological profile, indole got wider attention around the globe to explore it fully
in the interest of mankind. The current review covers recent advancements on indole in the
design of various anti-cancer agents acting by targeting various enzymes or receptors, including
(HDACs), sirtuins, PIM kinases, DNA topoisomerases, and σ receptors.
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Affiliation(s)
- Reyaz Hassan Mir
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar-190006, Kashmir, India
| | - Roohi Mohi-ud-din
- Pharmacognosy Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, 190006, Kashmir, India
| | - Taha Umair Wani
- Pharmaceutics Lab, Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Hazratbal, Srinagar-190006, Kashmir, India
| | - Mohammad Ovais Dar
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Abdul Jaleel Shah
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar-190006, Kashmir, India
| | - Bashir Lone
- Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India
| | - Chawla Pooja
- Department of Pharmaceutical Analysis, ISF College of Pharmacy, Moga-142001, India
| | - Mubashir Hussain Masoodi
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar-190006, Kashmir, India
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Agha H, McCurdy CR. In vitro and in vivo sigma 1 receptor imaging studies in different disease states. RSC Med Chem 2021; 12:154-177. [PMID: 34046607 PMCID: PMC8127618 DOI: 10.1039/d0md00186d] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 09/02/2020] [Indexed: 12/11/2022] Open
Abstract
The sigma receptor system has been classified into two distinct subtypes, sigma 1 (σ1R) and sigma 2 (σ2R). Sigma 1 receptors (σ1Rs) are involved in many neurodegenerative diseases and different central nervous system disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, and drug addiction, and pain. This makes them attractive targets for developing radioligands as tools to gain a better understanding of disease pathophysiology and clinical diagnosis. Over the years, several σ1R radioligands have been developed to image the changes in σ1R distribution and density providing insights into their role in disease development. Moreover, the involvement of both σ1Rs and σ2Rs with cancer make these ligands, especially those that are σ2R selective, great tools for imaging different types of tumors. This review will discuss the principles of molecular imaging using PET and SPECT, known σ1R radioligands and their applications for labelling σ1Rs under different disease conditions. Furthermore, this review will highlight σ1R radioligands that have demonstrated considerable potential as biomarkers, and an opportunity to fulfill the ultimate goal of better healthcare outcomes and improving human health.
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Affiliation(s)
- Hebaalla Agha
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida Gainesville FL 32610 USA +(352) 273 7705 +1 (352) 294 8691
| | - Christopher R McCurdy
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida Gainesville FL 32610 USA +(352) 273 7705 +1 (352) 294 8691
- UF Translational Drug Development Core, University of Florida Gainesville FL 32610 USA
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43
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Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, Rishton G, Safferstein H, Catalano SM. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson's patient brain-derived α-synuclein. J Neurosci Res 2021; 99:1161-1176. [PMID: 33480104 PMCID: PMC7986605 DOI: 10.1002/jnr.24782] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/03/2020] [Accepted: 12/13/2020] [Indexed: 12/11/2022]
Abstract
α‐Synuclein oligomers are thought to have a pivotal role in sporadic and familial Parkinson's disease (PD) and related α‐synucleinopathies, causing dysregulation of protein trafficking, autophagy/lysosomal function, and protein clearance, as well as synaptic function impairment underlying motor and cognitive symptoms of PD. Moreover, trans‐synaptic spread of α‐synuclein oligomers is hypothesized to mediate disease progression. Therapeutic approaches that effectively block α‐synuclein oligomer‐induced pathogenesis are urgently needed. Here, we show for the first time that α‐synuclein species isolated from human PD patient brain and recombinant α‐synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia, while α‐synuclein species isolated from non‐PD human control brain samples did not. Recombinant α‐synuclein oligomers also increased neuronal expression of lysosomal‐associated membrane protein‐2A (LAMP‐2A), the lysosomal receptor that has a critical role in chaperone‐mediated autophagy. Unbiased screening of several small molecule libraries (including the NIH Clinical Collection) identified sigma‐2 receptor antagonists as the most effective at blocking α‐synuclein oligomer‐induced trafficking deficits and LAMP‐2A upregulation in a dose‐dependent manner. These results indicate that antagonists of the sigma‐2 receptor complex may alleviate α‐synuclein oligomer‐induced neurotoxicity and are a novel therapeutic approach for disease modification in PD and related α‐synucleinopathies.
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Affiliation(s)
| | | | | | | | | | - Gary Look
- Cognition Therapeutics Inc., Pittsburgh, PA, USA
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Study of the Relationship between Sigma Receptor Expression Levels and Some Common Sigma Ligand Activity in Cancer Using Human Cancer Cell Lines of the NCI-60 Cell Line Panel. Biomedicines 2021; 9:biomedicines9010038. [PMID: 33466391 PMCID: PMC7824900 DOI: 10.3390/biomedicines9010038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 12/30/2020] [Indexed: 01/27/2023] Open
Abstract
Sigma (σ) receptors have attracted great interest since they are implicated in various cellular functions and biological processes and diseases, including various types of cancer. The receptor family consists of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). Both σ receptor subtypes have been proposed as therapeutic targets for various types of cancers, and many studies have provided evidence that their selective ligands (agonists and antagonists) exhibit antiproliferative and cytotoxic activity. Still, the precise mechanism of action of both σ receptors and their ligands remains unclear and needs to be elucidated. In this study, we aimed to simultaneously determine the expression levels of both σ receptor subtypes in several human cancer cell lines. Additionally, we investigated the in vitro antiproliferative activity of some widely used σ1 and σ2 ligands against those cell lines to study the relationship between σ receptor expression levels and σ ligand activity. Finally, we ran the NCI60 COMPARE algorithm to further elucidate the cytotoxic mechanism of action of the selected σ ligands studied herein.
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45
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Gagne C, Piot A, Brake WG. Depression, Estrogens, and Neuroinflammation: A Preclinical Review of Ketamine Treatment for Mood Disorders in Women. Front Psychiatry 2021; 12:797577. [PMID: 35115970 PMCID: PMC8804176 DOI: 10.3389/fpsyt.2021.797577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/24/2021] [Indexed: 12/11/2022] Open
Abstract
Ketamine has been shown to acutely and rapidly ameliorate depression symptoms and suicidality. Given that women suffer from major depression at twice the rate of men, it is important to understand how ketamine works in the female brain. This review explores three themes. First, it examines our current understanding of the etiology of depression in women. Second, it examines preclinical research on ketamine's antidepressant effects at a neurobiological level as well as how ovarian hormones present a unique challenge in interpreting these findings. Lastly, the neuroinflammatory hypothesis of depression is highlighted to help better understand how ovarian hormones might interact with ketamine in the female brain.
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Affiliation(s)
- Collin Gagne
- Department of Psychology, Centre for Studies in Behavioural Neurobiology Concordia University, Montreal, QC, Canada
| | - Alexandre Piot
- Department of Psychology, Centre for Studies in Behavioural Neurobiology Concordia University, Montreal, QC, Canada
| | - Wayne G Brake
- Department of Psychology, Centre for Studies in Behavioural Neurobiology Concordia University, Montreal, QC, Canada
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Xie XY, Li YY, Ma WH, Chen AF, Sun YT, Lee JY, Riad A, Xu DH, Mach RH, Huang YS. Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ 2R/TMEM97 ligands. Eur J Med Chem 2021; 209:112906. [PMID: 33049607 DOI: 10.1016/j.ejmech.2020.112906] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/01/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023]
Abstract
Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.
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Affiliation(s)
- Xiao-Yang Xie
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Yu-Yun Li
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Wen-Hui Ma
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Ai-Fang Chen
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Yu-Tong Sun
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Ji Youn Lee
- Department of Radiology, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA, 19104, USA
| | - Aladdin Riad
- Department of Radiology, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA, 19104, USA
| | - Dao-Hua Xu
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China
| | - Robert H Mach
- Department of Radiology, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA, 19104, USA.
| | - Yun-Sheng Huang
- School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
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Díaz JL, García M, Torrens A, Caamaño AM, Enjo J, Sicre C, Lorente A, Port A, Montero A, Yeste S, Álvarez I, Martín M, Maldonado R, de la Puente B, Vidal-Torres A, Cendán CM, Vela JM, Almansa C. EST64454: a Highly Soluble σ 1 Receptor Antagonist Clinical Candidate for Pain Management. J Med Chem 2020; 63:14979-14988. [PMID: 33237785 DOI: 10.1021/acs.jmedchem.0c01575] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone (9k, EST64454) as a σ1 receptor (σ1R) antagonist clinical candidate for the treatment of pain are reported. The compound 9k is easily obtained through a five-step synthesis suitable for the production scale and shows an outstanding aqueous solubility, which together with its high permeability in Caco-2 cells will allow its classification as a BCS class I compound. It also shows high metabolic stability in all species, linked to an adequate pharmacokinetic profile in rodents, and antinociceptive properties in the capsaicin and partial sciatic nerve ligation models in mice.
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Affiliation(s)
- José Luis Díaz
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Mónica García
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Antoni Torrens
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | | | - Juan Enjo
- Galchimia, S.A., Cebreiro, s/n, 15823 O Pino, A Coruña, Spain
| | - Cristina Sicre
- Galchimia, S.A., Cebreiro, s/n, 15823 O Pino, A Coruña, Spain
| | - Adriana Lorente
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Adriana Port
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Ana Montero
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Sandra Yeste
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Inés Álvarez
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Miquel Martín
- Laboratory of Neuropharmacology, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain
| | - Rafael Maldonado
- Laboratory of Neuropharmacology, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain
| | - Beatriz de la Puente
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Alba Vidal-Torres
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Cruz Miguel Cendán
- Department of Pharmacology, Faculty of Medicine, University of Granada, 18016 Granada, Spain
| | - José Miguel Vela
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
| | - Carmen Almansa
- ESTEVE Pharmaceuticals, Torre Esteve, Passeig de la Zona Franca, 109, 08038 Barcelona, Spain
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Abate C, Niso M, Abatematteo FS, Contino M, Colabufo NA, Berardi F. PB28, the Sigma-1 and Sigma-2 Receptors Modulator With Potent Anti-SARS-CoV-2 Activity: A Review About Its Pharmacological Properties and Structure Affinity Relationships. Front Pharmacol 2020; 11:589810. [PMID: 33364961 PMCID: PMC7750835 DOI: 10.3389/fphar.2020.589810] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/15/2020] [Indexed: 12/27/2022] Open
Abstract
These unprecedented times have forced the scientific community to gather to face the COVID-19 pandemic. Efforts in diverse directions have been made. A multi-university team has focused on the identification of the host (human) proteins interacting with SARS-CoV-2 viral proteins, with the aim of hampering these interactions that may cause severe COVID-19 symptoms. Sigma-1 and sigma-2 receptors surprisingly belong to the “druggable” host proteins found, with the pan-sigma receptor modulator PB28 displaying the most potent anti–SARS-CoV-2 activity in in vitro assays. Being 20-fold more active than hydroxychloroquine, without cardiac side effects, PB28 is a promising antiviral candidate worthy of further investigation. Our research group developed PB28 in 1996 and have thoroughly characterized its biological properties since then. Structure–affinity relationship (SAfiR) studies at the sigma receptor subtypes were also undertaken with PB28 as the lead compound. We herein report our knowledge of PB28 to share information that may help to gain insight into the antiviral action of this compound and sigma receptors, while providing structural hints that may speed up the translation into therapeutics of this class of ligands.
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Affiliation(s)
- Carmen Abate
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Bari, Italy
| | - Mauro Niso
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Bari, Italy
| | | | - Marialessandra Contino
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Bari, Italy
| | - Nicola Antonio Colabufo
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Bari, Italy
| | - Francesco Berardi
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Bari, Italy
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Sigma-2 Receptor-A Potential Target for Cancer/Alzheimer's Disease Treatment via Its Regulation of Cholesterol Homeostasis. Molecules 2020; 25:molecules25225439. [PMID: 33233619 PMCID: PMC7699687 DOI: 10.3390/molecules25225439] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/10/2020] [Accepted: 11/19/2020] [Indexed: 12/17/2022] Open
Abstract
The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of the biological and pharmacological properties of the sigma-1 receptor is increasing; however, little is known about the sigma-2 receptor. Recently, the molecular identity of the sigma-2 receptor has been identified as TMEM97. Although more and more evidence has showed that sigma-2 ligands have the ability to treat cancer and Alzheimer’s disease (AD), the mechanisms connecting these two diseases are unknown. Data obtained over the past few years from human and animal models indicate that cholesterol homeostasis is altered in AD and cancer, underscoring the importance of cholesterol homeostasis in AD and cancer. In this review, based on accumulated evidence, we proposed that the beneficial roles of sigma-2 ligands in cancer and AD might be mediated by their regulation of cholesterol homeostasis.
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50
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Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease. eNeuro 2020; 7:ENEURO.0317-20.2020. [PMID: 33028631 PMCID: PMC7643771 DOI: 10.1523/eneuro.0317-20.2020] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/10/2020] [Accepted: 09/12/2020] [Indexed: 01/04/2023] Open
Abstract
The σ-2 receptor (S2R) complex has been implicated in CNS disorders ranging from anxiety and depression to neurodegenerative disorders such as Alzheimer's disease (AD). The proteins comprising the S2R complex impact processes including autophagy, cholesterol synthesis, progesterone signaling, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. While there has been much progress in understanding the role of S2R in cellular processes and its potential therapeutic value, a great deal remains unknown. The International Symposium on Sigma-2 Receptors is held in conjunction with the annual Society for Neuroscience (SfN) conference to promote collaboration and advance the field of S2R research. This review summarizes updates presented at the Fourth International Symposium on Sigma-2 Receptors: Role in Health and Disease, a Satellite Symposium held at the 2019 SfN conference. Interdisciplinary members of the S2R research community presented both previously published and preliminary results from ongoing studies of the role of S2R in cellular metabolism, the anatomic and cellular expression patterns of S2R, the relationship between S2R and amyloid β (Aβ) in AD, the role of S2R complex protein PGRMC1 in health and disease, and the efforts to design new S2R ligands for the purposes of research and drug development. The proceedings from this symposium are reported here as an update on the field of S2R research, as well as to highlight the value of the symposia that occur yearly in conjunction with the SfN conference.
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