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1
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Tiligada E, Stefanaki C, Ennis M, Neumann D. Opportunities and challenges in the therapeutic exploitation of histamine and histamine receptor pharmacology in inflammation-driven disorders. Pharmacol Ther 2024; 263:108722. [PMID: 39306197 DOI: 10.1016/j.pharmthera.2024.108722] [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: 05/24/2024] [Revised: 07/31/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024]
Abstract
Inflammation-driven diseases encompass a wide array of pathological conditions characterised by immune system dysregulation leading to tissue damage and dysfunction. Among the myriad of mediators involved in the regulation of inflammation, histamine has emerged as a key modulatory player. Histamine elicits its actions through four rhodopsin-like G-protein-coupled receptors (GPCRs), named chronologically in order of discovery as histamine H1, H2, H3 and H4 receptors (H1-4R). The relatively low affinity H1R and H2R play pivotal roles in mediating allergic inflammation and gastric acid secretion, respectively, whereas the high affinity H3R and H4R are primarily linked to neurotransmission and immunomodulation, respectively. Importantly, however, besides the H4R, both H1R and H2R are also crucial in driving immune responses, the H2R tending to promote yet ill-defined and unexploited suppressive, protective and/or resolving processes. The modulatory action of histamine via its receptors on inflammatory cells is described in detail. The potential therapeutic value of the most recently discovered H4R in inflammatory disorders is illustrated via a selection of preclinical models. The clinical trials with antagonists of this receptor are discussed and possible reasons for their lack of success described.
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Affiliation(s)
- Ekaterini Tiligada
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - Charikleia Stefanaki
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; University Research Institute of Maternal and Child Health and Precision Medicine, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Madeleine Ennis
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast, Belfast, UK
| | - Detlef Neumann
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
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2
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Sahiba N, Teli P, Meena P, Agarwal S. Exploring the Synthetic and Antioxidant Potential of 1,2-Disubstituted Benzimidazoles Using [Et 3NH][HSO 4] Ionic Liquid Catalyst. Chem Biodivers 2024; 21:e202301159. [PMID: 37718514 DOI: 10.1002/cbdv.202301159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/13/2023] [Accepted: 09/17/2023] [Indexed: 09/19/2023]
Abstract
An [Et3NH][HSO4] ionic-liquid catalyzed, intermolecular C-N bond formation for 1,2-disubstituted benzimidazole synthesis was achieved by the reaction of OPD and substituted aldehydes at ambient reaction conditions. Operational simplicity, use of easily available substrate and reagents, good yields (74-95 %) in short reaction time (4-18 min), simple work-up, and column chromatographic free synthesis are the remarkable features of this new protocol. The applicability of [Et3NH][HSO4] ionic-liquid as a green and inexpensive catalyst with good recyclability and compatibility with a broad range of functional group having heteroatom, electron-withdrawing, and electron-releasing groups manifested the sustainability, eco-friendliness, and efficiency of the present methodology. Moreover, the antioxidant studies of the synthesized compounds using DPPH and ABTS assays were appealing and several synthesized compounds showed significant antioxidant activity.
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Affiliation(s)
- Nusrat Sahiba
- Synthetic Organic Chemistry Lab, Department of Chemistry, MLSU, Udaipur, 313001, Rajasthan, India
| | - Pankaj Teli
- Synthetic Organic Chemistry Lab, Department of Chemistry, MLSU, Udaipur, 313001, Rajasthan, India
| | - Priyadarshi Meena
- Cancer Biology Lab, Department of Zoology, University of Rajasthan, Jaipur, 302004, Rajasthan, India
| | - Shikha Agarwal
- Synthetic Organic Chemistry Lab, Department of Chemistry, MLSU, Udaipur, 313001, Rajasthan, India
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3
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Im D, Kishikawa JI, Shiimura Y, Hisano H, Ito A, Fujita-Fujiharu Y, Sugita Y, Noda T, Kato T, Asada H, Iwata S. Structural insights into the agonists binding and receptor selectivity of human histamine H 4 receptor. Nat Commun 2023; 14:6538. [PMID: 37863901 PMCID: PMC10589313 DOI: 10.1038/s41467-023-42260-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 10/04/2023] [Indexed: 10/22/2023] Open
Abstract
Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H4 receptor (H4R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H4R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe3447.39, which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of H4R and subtype selectivity of histamine receptors, and show that the H4R structures may be valuable in rational drug design of drugs targeting the H4R.
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Affiliation(s)
- Dohyun Im
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Jun-Ichi Kishikawa
- Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Shiimura
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan
- Institute of Life Science, Kurume University, Kurume, Fukuoka, 830-0011, Japan
| | - Hiromi Hisano
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Akane Ito
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yoko Fujita-Fujiharu
- Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
- Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
- CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
| | - Yukihiko Sugita
- Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
- Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
- Hakubi Center for Advanced Research, Kyoto University, Kyoto, 606-8501, Japan
| | - Takeshi Noda
- Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
- Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
- CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
| | - Takayuki Kato
- Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Hidetsugu Asada
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
| | - So Iwata
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
- RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, 679-5148, Japan.
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4
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Olejarz-Maciej A, Mogilski S, Karcz T, Werner T, Kamińska K, Kupczyk J, Honkisz-Orzechowska E, Latacz G, Stark H, Kieć-Kononowicz K, Łażewska D. Trisubstituted 1,3,5-Triazines as Histamine H 4 Receptor Antagonists with Promising Activity In Vivo. Molecules 2023; 28:molecules28104199. [PMID: 37241939 DOI: 10.3390/molecules28104199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H4 receptor (H4R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H4R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H4R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H4R. The majority of compounds showed a moderate affinity for this receptor (Ki > 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound 6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; Ki = 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; Pe = 12.26 × 10-6 cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound 6 tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound 6 at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound 6 is a promising ligand for further studies.
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Affiliation(s)
- Agnieszka Olejarz-Maciej
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Szczepan Mogilski
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Tadeusz Karcz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Tobias Werner
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
| | - Katarzyna Kamińska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Jarosław Kupczyk
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Ewelina Honkisz-Orzechowska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Gniewomir Latacz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
| | - Katarzyna Kieć-Kononowicz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
| | - Dorota Łażewska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland
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5
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Strzelec M, Detka J, Mieszczak P, Sobocińska MK, Majka M. Immunomodulation—a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol 2023; 14:1127704. [PMID: 36969193 PMCID: PMC10033545 DOI: 10.3389/fimmu.2023.1127704] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/23/2023] [Indexed: 03/11/2023] Open
Abstract
In recent years, there has been a tremendous development of biotechnological, pharmacological, and medical techniques which can be implemented in the functional modulation of the immune system components. Immunomodulation has attracted much attention because it offers direct applications in both basic research and clinical therapy. Modulation of a non-adequate, amplified immune response enables to attenuate the clinical course of a disease and restore homeostasis. The potential targets to modulate immunity are as multiple as the components of the immune system, thus creating various possibilities for intervention. However, immunomodulation faces new challenges to design safer and more efficacious therapeutic compounds. This review offers a cross-sectional picture of the currently used and newest pharmacological interventions, genomic editing, and tools for regenerative medicine involving immunomodulation. We reviewed currently available experimental and clinical evidence to prove the efficiency, safety, and feasibility of immunomodulation in vitro and in vivo. We also reviewed the advantages and limitations of the described techniques. Despite its limitations, immunomodulation is considered as therapy itself or as an adjunct with promising results and developing potential.
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6
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Zhang S, Liu Y, Javeed A, Jian C, Sun J, Wu S, Han B. Treatment of allergy: Overview of synthetic anti-allergy small molecules in medicinal chemistry. Eur J Med Chem 2023; 249:115151. [PMID: 36731273 DOI: 10.1016/j.ejmech.2023.115151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 01/30/2023]
Abstract
The prevalence of allergic diseases has been continuously increasing over the past few decades, affecting approximately 20-30% of the global population. Allergic reactions to infection of respiratory tract, digestive tract, and skin system involve multiple different targets. The main difficulty of anti-allergy research is how to develop drugs with good curative effect and less side effects by adopting new multi-targets and mechanisms according to the clinical characteristics of different allergic populations and different allergens. This review focuses on information concerning potential therapeutic targets as well as the synthetic anti-allergy small molecules with respect to their medicinal chemistry. The structure-activity relationship and the mechanism of compound-target interaction were highlighted with perspective to histamine-1/4 receptor antagonists, leukotriene biosynthesis, Th2 cytokines inhibitors, and calcium channel blockers. We hope that the study of chemical scaffold modification and optimization for different lead compounds summarized in this review not only lays the foundation for improvement of success rate and efficiency of virtual screening of antiallergic drugs, but also can provide valuable reference for the drug design of related promising research such as allergy, inflammation, and cancer.
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Affiliation(s)
- Shanshan Zhang
- Zhejiang Key Laboratory of Silkworm Bioreactor and Biomedicine, Laboratory of Antiallergy Functional Molecules, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Yi Liu
- Hangzhou Zheda Dixun Biological Gene Engineering Co., LTD., Hangzhou, China
| | - Ansar Javeed
- Zhejiang Key Laboratory of Silkworm Bioreactor and Biomedicine, Laboratory of Antiallergy Functional Molecules, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Cuiqin Jian
- Zhejiang Key Laboratory of Silkworm Bioreactor and Biomedicine, Laboratory of Antiallergy Functional Molecules, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Jinlyu Sun
- Department of Allergy, Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment of Allergic Diseases, National Clinical Research Center for Dermatologic and Immunologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Shandong Wu
- Hangzhou Zheda Dixun Biological Gene Engineering Co., LTD., Hangzhou, China
| | - Bingnan Han
- Zhejiang Key Laboratory of Silkworm Bioreactor and Biomedicine, Laboratory of Antiallergy Functional Molecules, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
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7
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Mochizuki H, Suyama S, Youm SY, Ho PS, Shimoi A. Characteristics of histamine H 4 receptor agonist-induced allergic conjunctivitis model in Guinea pigs. J Pharmacol Toxicol Methods 2023; 119:107203. [PMID: 35842185 DOI: 10.1016/j.vascn.2022.107203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 01/03/2023]
Abstract
Histamine is strongly associated with the onset of allergic conjunctivitis. The most recent cloned histamine H4 receptor antagonist is highly expected as a new therapeutic drug candidate. As a model for a therapeutic drug targeting the histamine H4 receptor, a mouse model in which conjunctivitis symptoms are induced by instilling 4-methylhistamine, a histamine H4 receptor agonist, has been reported. However, the affinity of the H4 receptor for histamine varies in species, and it is known that the histamine binding affinity for the guinea pig H4 receptor is closer to that for human receptor than mice receptor. In this paper, we investigated a possibility that a guinea pig model would become a drug efficacy evaluation model with higher evaluation accuracy than the mouse model. As a result, hyperemia was observed in the conjunctivae and iris of guinea pigs after instillation of 4-methylhistamine and specifically suppressed by the histamine H4 receptor antagonist. Unlikely to the previously reported mouse model, however, none of edema, increased vascular permeability or scratching behavior was observed, suggesting that there may be differences between mice and guinea pigs not only in the binding affinity of histamine to the H4 receptor but also in the biological reaction to 4-methylhistamine. Although the symptoms of allergic conjunctivitis do not appear comprehensively in the guinea pig model, results of this study indicated a possibility that this model can be used as a simple screening model in the early stages of drug development.
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Affiliation(s)
- Hidemi Mochizuki
- Ina Research Inc., 2148-188 Nishiminowa, Ina, Nagano 399-4501, Japan.
| | - Susumu Suyama
- Ina Research Inc., 2148-188 Nishiminowa, Ina, Nagano 399-4501, Japan.
| | - So-Young Youm
- JW Pharmaceutical Corporation, 2477, Nambusunhwan-ro, Seocho-gu, Seoul, 137-864, Republic of Korea.
| | - Pil-Su Ho
- JW Pharmaceutical Corporation, 2477, Nambusunhwan-ro, Seocho-gu, Seoul, 137-864, Republic of Korea.
| | - Akihito Shimoi
- Ina Research Inc., 2148-188 Nishiminowa, Ina, Nagano 399-4501, Japan.
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Falkenstein M, Elek M, Stark H. Chemical Probes for Histamine Receptor Subtypes. Curr Top Behav Neurosci 2021; 59:29-76. [PMID: 34595743 DOI: 10.1007/7854_2021_254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Ligands with different properties and different selectivity are highly needed for in vitro and in vivo studies on the (patho)physiological influence of the chemical mediator histamine and its receptor subtypes. A selection of well-described ligands for the different receptor subtypes and different studies is shown with a particular focus on affinity and selectivity. In addition, compounds with radioactive or fluorescence elements will be presented with their beneficial use for other species or different investigations.
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Affiliation(s)
- Markus Falkenstein
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf, Germany
| | - Milica Elek
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf, Germany
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf, Germany.
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9
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Zak A, Lemaire L, Chalon S, Chicheri G, Marzag H, Bodard S, Sérrière S, Routier S, Buron F, Vercouillie J. [ 18 F]-labeled positron emission tomography ligand for the histamine H4 receptor. J Labelled Comp Radiopharm 2021; 64:363-372. [PMID: 34089268 DOI: 10.1002/jlcr.3929] [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: 05/19/2020] [Revised: 05/18/2021] [Accepted: 05/28/2021] [Indexed: 11/10/2022]
Abstract
We synthesized 5-[18 F]-fluoro-1H-indol-2-yl)(4-methyl-1-piperazinyl)methanone ([18 F]5) via a Suzuki approach starting from a protected pinacol borane precursor followed by acidic hydrolysis of the t-Boc protecting group. The non-optimized radiochemical yield was 5.7 ± 1.35%, radiochemical purity was over 99%, and molar activity was 100.7 ± 34.5 GBq/μmol (n = 3). [18 F]5 was stable in rat plasma for at least 4 h and was evaluated by μPET imaging and biodistribution using a unilateral quinolinic acid rat model of neuroinflammation. The time-activity curve showed that [18 F]5 entered the brain immediately after intravenous injection and then left it progressively with a very low level reached from 30 min after injection. The biodistribution study showed no difference in the accumulation of [18 F]5 between the lesioned and intact side of the brain and between control rats and animals pretreated with a saturating dose of JNJ-7777120 as a specific H4R antagonist. Hence, despite its in vitro nanomolar affinity for H4R, and its ability to cross the blood-brain barrier in rats, [18 F]5 does not appear suitable to image in vivo the receptor by PET.
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Affiliation(s)
- Agnieszka Zak
- Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orléans, France
| | - Lucas Lemaire
- Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orléans, France
| | - Sylvie Chalon
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
| | - Gabrielle Chicheri
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
- CERRP, Université de Tours, Tours, France
| | - Hamid Marzag
- Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orléans, France
| | - Sylvie Bodard
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
| | - Sophie Sérrière
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
| | - Sylvain Routier
- Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orléans, France
| | - Frédéric Buron
- Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orléans, France
| | - Johnny Vercouillie
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
- CERRP, Université de Tours, Tours, France
- INSERM CIC 1415, University Hospital, Tours, France
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10
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Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H 3 and H 4 receptors. Bioorg Med Chem 2020; 30:115924. [PMID: 33333448 DOI: 10.1016/j.bmc.2020.115924] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/28/2020] [Accepted: 12/01/2020] [Indexed: 01/18/2023]
Abstract
Histamine acts through four different receptors (H1R-H4R), the H3R and H4R being the most explored in the last years as drug targets. The H3R is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while H4R blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human H3R/H4R ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hH3R affinity (pKi > 7), compound 1h being the most potent (pKi 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gαi activity indicated that the compounds are potent antagonists. Only one compound (2c, pKi 7.1) presented high affinity for hH4R. In contrast to what was observed for hH3R, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hH3R, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hH3R. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hH4R was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hH3R and hH4R.
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11
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Höring C, Seibel U, Tropmann K, Grätz L, Mönnich D, Pitzl S, Bernhardt G, Pockes S, Strasser A. A Dynamic, Split-Luciferase-Based Mini-G Protein Sensor to Functionally Characterize Ligands at All Four Histamine Receptor Subtypes. Int J Mol Sci 2020; 21:ijms21228440. [PMID: 33182741 PMCID: PMC7698210 DOI: 10.3390/ijms21228440] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/06/2020] [Accepted: 11/08/2020] [Indexed: 02/06/2023] Open
Abstract
In drug discovery, assays with proximal readout are of great importance to study target-specific effects of potential drug candidates. In the field of G protein-coupled receptors (GPCRs), the determination of GPCR-G protein interactions and G protein activation by means of radiolabeled GTP analogs ([35S]GTPγS, [γ-32P]GTP) has widely been used for this purpose. Since we were repeatedly faced with insufficient quality of radiolabeled nucleotides, there was a requirement to implement a novel proximal functional assay for the routine characterization of putative histamine receptor ligands. We applied the split-NanoLuc to the four histamine receptor subtypes (H1R, H2R, H3R, H4R) and recently engineered minimal G (mini-G) proteins. Using this method, the functional response upon receptor activation was monitored in real-time and the four mini-G sensors were evaluated by investigating selected standard (inverse) agonists and antagonists. All potencies and efficacies of the studied ligands were in concordance with literature data. Further, we demonstrated a significant positive correlation of the signal amplitude and the mini-G protein expression level in the case of the H2R, but not for the H1R or the H3R. The pEC50 values of histamine obtained under different mini-G expression levels were consistent. Moreover, we obtained excellent dynamic ranges (Z’ factor) and the signal spans were improved for all receptor subtypes in comparison to the previously performed [35S]GTPγS binding assay.
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Affiliation(s)
- Carina Höring
- Correspondence: (C.H.); , (A.S.); Tel.: +49-941-943-4748 (C.H.); +49-941-943-4821 (A.S.)
| | | | | | | | | | | | | | | | - Andrea Strasser
- Correspondence: (C.H.); , (A.S.); Tel.: +49-941-943-4748 (C.H.); +49-941-943-4821 (A.S.)
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12
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Grosicki M, Adami M, Micheloni C, Głuch-Lutwin M, Siwek A, Latacz G, Łażewska D, Więcek M, Reiner-Link D, Stark H, Chlopicki S, Kieć-Kononowicz K. Eosinophils adhesion assay as a tool for phenotypic drug screening - The pharmacology of 1,3,5 - Triazine and 1H-indole like derivatives against the human histamine H 4 receptor. Eur J Pharmacol 2020; 890:173611. [PMID: 33017589 DOI: 10.1016/j.ejphar.2020.173611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/22/2020] [Accepted: 09/28/2020] [Indexed: 11/18/2022]
Abstract
Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H4 receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H4 receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H4 receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H4 receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H4 receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.
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Key Words
- 1,3,5 – Triazine derivatives
- 1H-Indole like derivatives
- 1H-indole like derivatives
- Adhesion
- Endothelium
- Eosinophils
- Histamine
- Histamine receptors
- JN-25 (4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine)
- JN-35 (4-(4-methylpiperazin-1-yl)-6-(3-phenylpropyl)-1,3,5-triazin-2-amine)
- JNJ10191584 (5-chloro-1H-benzo[d]imidazol-2-yl)(4-methylpiperazin-1-yl)methanone) Pub- Chem CID: 10446295)
- JNJ7777120 (5-chloro-1H-indol-2-yl)(4-methylpiperazin-1-yl)methanone) Pub- Chem CID: 4908365)
- KP-9D (2-(4-chlorophenyl)-4-(4-methylpiperazin-1-yl)-1,3,5-triazine)
- MWJ-3 (5-chloro-7-nitro-1H-indol-2-yl)(4-methylpiperazin-1-yl)methanone Pub- Chem CID: 70692530)
- TR-18 (4-(4-bromophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine)
- TR-7 (4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine)
- TR-AF-45 (4-(4-methylpiperazin-1-yl)-6-neopentyl-1,3,5-triazin-2-amine)
- TR-AF-49 (4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine)
- TR-DL-20 (4-(1-cyclohexenylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine)
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Affiliation(s)
- Marek Grosicki
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland; Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, 30-348, Krakow, Poland
| | - Maristella Adami
- University of Parma, Department of Medicine and Surgery, Via Gramsci 14, 43126, Parma, Italy
| | - Cristina Micheloni
- University of Parma, Department of Medicine and Surgery, Via Gramsci 14, 43126, Parma, Italy
| | - Monika Głuch-Lutwin
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacobiology, Medyczna 9, 30-688, Kraków, Poland
| | - Agata Siwek
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacobiology, Medyczna 9, 30-688, Kraków, Poland
| | - Gniewomir Latacz
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland
| | - Dorota Łażewska
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland
| | - Małgorzata Więcek
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland
| | - David Reiner-Link
- Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitätsstraße 1, 40225, Duesseldorf, Germany
| | - Holger Stark
- Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitätsstraße 1, 40225, Duesseldorf, Germany
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzyńskiego 14, 30-348, Krakow, Poland; Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531, Krakow, Poland
| | - Katarzyna Kieć-Kononowicz
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland.
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13
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Bartole E, Grätz L, Littmann T, Wifling D, Seibel U, Buschauer A, Bernhardt G. UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H3 and H4 Receptors. J Med Chem 2020; 63:5297-5311. [DOI: 10.1021/acs.jmedchem.0c00160] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Edith Bartole
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
| | - Lukas Grätz
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
| | - Timo Littmann
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
| | - David Wifling
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
| | - Ulla Seibel
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
| | - Armin Buschauer
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
| | - Günther Bernhardt
- Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany
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14
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Nagarajan G, Thangam EB. Effect of H4R Antagonist N-(2-Aminoethyl)-5-Chloro-1H-Indole-2-Carboxamide (Compound A) in a Mouse Model of Allergic Asthma. Immunol Invest 2020; 50:125-138. [PMID: 31985316 DOI: 10.1080/08820139.2020.1712415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Context: Allergic asthma is a multifactorial airway disease characterised by chronic lung inflammation and airway remodelling. The histamine H4 receptor involved in the chemotaxis of leukocytes and mast cells to the site of inflammation is suggested to be a potential drug target for allergy and asthma. In this study we examined the effect of Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide a H4 receptor antagonist in allergic asthma mice model. Objective: To investigate the anti-asthmatic effect of compound A in in vivo, airway inflammation in ovalbumin (OVA) induced allergic asthma mouse model was used. Methodology: Allergic asthma was induced in Balb/c mice using ovalbumin. BAL fluid was examined for the level of IgE, IL-4, IL-5, IL-13 and IL-17 using ELISA. Furthermore, infiltration of leucocytes by histopathology and effect of compound A on signalling molecules were examined in lung tissue. Results: In mice pre-treatment with compound A (10 mg/kg, 20 mg/kg, 30 mg/kg) at different concentrations markedly reduced the levels of IgE, Th2 cytokine IL-4, IL-5, IL-13 and Th17 cytokine IL-17 in BAL fluid. Histopathological examination of lung tissue showed that compound A was able to reduce the level of inflammatory infiltrates. Furthermore, lung tissue from Compound A treated group shown to down-regulate the levels of signalling molecules such as ERK1/2, Akt, SAPK/JNK and NF-κB compared to OVA treated group. Discussion and conclusion: Taken together our data demonstrates that compound A has shown to block the H4R-mediated allergic inflammation in this allergic asthma mice model and may be used as a molecule to study the function of H4R. Abbreviations: Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide; JNJ7777120, 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine; H4R: Histamine 4 Receptor; AHR: Airway hyper responsiveness.
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Affiliation(s)
- Gomathi Nagarajan
- Department of Biotechnology, School of Bioengineering, SRM Institue of Science and Technology , Kattankulathur, India
| | - Elden Berla Thangam
- Department of Biotechnology, School of Bioengineering, SRM Institue of Science and Technology , Kattankulathur, India
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15
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Domínguez‐Álvarez E, Łażewska D, Szabó Z, Hagenow S, Reiner D, Gajdács M, Spengler G, Stark H, Handzlik J, Kieć‐Kononowicz K. The Search for Histamine H
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Receptor Ligands with Anticancer Activity among Novel (Thio)urea Derivatives. ChemistrySelect 2019. [DOI: 10.1002/slct.201902747] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Enrique Domínguez‐Álvarez
- Instituto de Química Orgánica GeneralConsejo Superior de Investigaciones Científicas (IQOG-CSIC) Juan de la Cierva 3 28006 Madrid Spain
| | - Dorota Łażewska
- Department of Technology and Biotechnology of DrugsFaculty of PharmacyJagiellonian University Medical College 9 Medyczna Street 30-688 Kraków Poland
| | - Zsanett Szabó
- Department of Medical Microbiology and ImmunobiologyFaculty of MedicineUniversity of Szeged Dóm tér 10 6720 Szeged Hungary
| | - Stefanie Hagenow
- Institute of Pharmaceutical and Medicinal ChemistryHeinrich Heine University Düsseldorf Universitätsstraße 1 40225 Düsseldorf
| | - David Reiner
- Institute of Pharmaceutical and Medicinal ChemistryHeinrich Heine University Düsseldorf Universitätsstraße 1 40225 Düsseldorf
| | - Márió Gajdács
- Department of Medical Microbiology and ImmunobiologyFaculty of MedicineUniversity of Szeged Dóm tér 10 6720 Szeged Hungary
| | - Gabriella Spengler
- Department of Medical Microbiology and ImmunobiologyFaculty of MedicineUniversity of Szeged Dóm tér 10 6720 Szeged Hungary
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal ChemistryHeinrich Heine University Düsseldorf Universitätsstraße 1 40225 Düsseldorf
| | - Jadwiga Handzlik
- Department of Technology and Biotechnology of DrugsFaculty of PharmacyJagiellonian University Medical College 9 Medyczna Street 30-688 Kraków Poland
| | - Katarzyna Kieć‐Kononowicz
- Department of Technology and Biotechnology of DrugsFaculty of PharmacyJagiellonian University Medical College 9 Medyczna Street 30-688 Kraków Poland
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16
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Bartole E, Littmann T, Tanaka M, Ozawa T, Buschauer A, Bernhardt G. [ 3H]UR-DEBa176: A 2,4-Diaminopyrimidine-Type Radioligand Enabling Binding Studies at the Human, Mouse, and Rat Histamine H 4 Receptors. J Med Chem 2019; 62:8338-8356. [PMID: 31469288 DOI: 10.1021/acs.jmedchem.9b01342] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Differences in sequence homology between human (h), mouse (m), and rat (r) histamine H4 receptors (H4R) cause discrepancies regarding affinities, potencies, and/or efficacies of ligands and therefore compromise translational animal models and the applicability of radioligands. Aiming at a radioligand enabling robust and comparative binding studies at the h/m/rH4Rs, 2,4-diaminopyrimidines were synthesized and pharmacologically investigated. The most notable compounds identified were two (partial) agonists with comparable potencies at the h/m/rH4Rs: UR-DEBa148 (N-neopentyl-4-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate), 43), the most potent [pEC50 (reporter gene assay) = 9.9/9.6/10.3] compound in the series being slightly G-protein biased and UR-DEBa176 [(R)-4-[3-(dimethylamino)pyrrolidin-1-yl]-N-neopentylpyrimidin-2-amine bis(2,2,2-trifluoroacetate), 46, pEC50 (reporter gene assay) = 8.7/9.0/9.2], a potential "cold" form of a tritiated H4R ligand. After radiolabeling, binding studies with [3H]UR-DEBa176 ([3H]46) at the h/m/rH4Rs revealed comparable Kd values (41/17/22 nM), low nonspecific binding (11-17%, ∼Kd), and fast associations/dissociations (25-30 min) and disclosed [3H]UR-DEBa176 as useful molecular tool to determine h/m/rH4R binding affinities for H4R ligands.
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Affiliation(s)
- Edith Bartole
- Institute of Pharmacy , University of Regensburg , D-93053 Regensburg , Germany
| | - Timo Littmann
- Institute of Pharmacy , University of Regensburg , D-93053 Regensburg , Germany
| | - Miho Tanaka
- Department of Chemistry, School of Science , University of Tokyo , 7-3-1 Bunkyo-ku , Hongo , Tokyo 113-0033 , Japan
| | - Takeaki Ozawa
- Department of Chemistry, School of Science , University of Tokyo , 7-3-1 Bunkyo-ku , Hongo , Tokyo 113-0033 , Japan
| | - Armin Buschauer
- Institute of Pharmacy , University of Regensburg , D-93053 Regensburg , Germany
| | - Günther Bernhardt
- Institute of Pharmacy , University of Regensburg , D-93053 Regensburg , Germany
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17
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Histamine, histamine receptors, and anti-histamines in the context of allergic responses. LYMPHOSIGN JOURNAL 2019. [DOI: 10.14785/lymphosign-2018-0016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Histamine is a bioactive amine which is considered a key player in the allergic response. Thus, histamine receptor blockers (antihistamines) play an important role in the treatment of a number atopic diseases such as allergic rhinitis, conjunctivitis, and acute and chronic forms of urticaria. Histamine is produced by immune cells but also by bacteria in the gut. Beyond its role in the acute allergic response, histamine exerts numerous effects by binding to its 4 pleiotropic G-protein coupled histamine receptors. Here, we describe the roles of these histamine receptors and antihistamines in the human system, clinical applications, side effects, and novel concepts for the usage of antihistamines with different specificity based on guidelines and recommendations. Statement of novelty: This review provides an overview of histamine receptors and links it to clinical relevance of antagonizing their action in clinical routine.
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18
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Alkyl derivatives of 1,3,5-triazine as histamine H4 receptor ligands. Bioorg Med Chem 2019; 27:1254-1262. [DOI: 10.1016/j.bmc.2019.02.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/31/2019] [Accepted: 02/11/2019] [Indexed: 12/21/2022]
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19
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Tatarkiewicz J, Rzodkiewicz P, Żochowska M, Staniszewska A, Bujalska-Zadrożny M. New antihistamines - perspectives in the treatment of some allergic and inflammatory disorders. Arch Med Sci 2019; 15:537-553. [PMID: 30899308 PMCID: PMC6425212 DOI: 10.5114/aoms.2017.68534] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 03/13/2017] [Indexed: 12/29/2022] Open
Affiliation(s)
- Jan Tatarkiewicz
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Przemysław Rzodkiewicz
- Department of Biochemistry and Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
- Department of General and Experimental Pathology, Medical University of Warsaw, Warsaw, Poland
| | - Małgorzata Żochowska
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Staniszewska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Bujalska-Zadrożny
- Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
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20
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Pockes S, Wifling D, Buschauer A, Elz S. Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands †. ChemistryOpen 2019; 8:285-297. [PMID: 30886786 PMCID: PMC6401531 DOI: 10.1002/open.201900011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/08/2019] [Indexed: 11/05/2022] Open
Abstract
New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S-methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.
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Affiliation(s)
- Steffen Pockes
- Institute of Pharmacy, Faculty of Chemistry and PharmacyUniversity of RegensburgUniversitätsstraße 31D-93053RegensburgGermany
| | - David Wifling
- Institute of Pharmacy, Faculty of Chemistry and PharmacyUniversity of RegensburgUniversitätsstraße 31D-93053RegensburgGermany
| | - Armin Buschauer
- Institute of Pharmacy, Faculty of Chemistry and PharmacyUniversity of RegensburgUniversitätsstraße 31D-93053RegensburgGermany
| | - Sigurd Elz
- Institute of Pharmacy, Faculty of Chemistry and PharmacyUniversity of RegensburgUniversitätsstraße 31D-93053RegensburgGermany
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21
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Tiligada E, Ennis M. Histamine pharmacology: from Sir Henry Dale to the 21st century. Br J Pharmacol 2018; 177:469-489. [PMID: 30341770 DOI: 10.1111/bph.14524] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 09/30/2018] [Accepted: 10/08/2018] [Indexed: 12/28/2022] Open
Abstract
Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory functions by activating four types of GPCRs, designated as H1-4 . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H1 antihistamines and H2 -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders respectively. Recently, a first-in-class H3 inverse agonist was approved for the treatment of narcolepsy, whereas H4 antagonists are under clinical evaluation for their potential therapeutic exploitation in immune-related diseases. This review critically presents the past successes and drawbacks in histamine research, complemented by the modern conceptual innovations in molecular and receptor pharmacology. It targets both young and experienced researchers in an ongoing effort to stimulate novel insights for the dissection of the translational potential of histamine pharmacology. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
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Affiliation(s)
- Ekaterini Tiligada
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Madeleine Ennis
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
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22
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Mocking TAM, Verweij EWE, Vischer HF, Leurs R. Homogeneous, Real-Time NanoBRET Binding Assays for the Histamine H 3 and H 4 Receptors on Living Cells. Mol Pharmacol 2018; 94:1371-1381. [PMID: 30249614 DOI: 10.1124/mol.118.113373] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 09/19/2018] [Indexed: 11/22/2022] Open
Abstract
Receptor-binding affinity and ligand-receptor residence time are key parameters for the selection of drug candidates and are routinely determined using radioligand competition-binding assays. Recently, a novel bioluminescence resonance energy transfer (BRET) method utilizing a NanoLuc-fused receptor was introduced to detect fluorescent ligand binding. Moreover, this NanoBRET method gives the opportunity to follow fluorescent ligand binding on intact cells in real time, and therefore, results might better reflect in vivo conditions as compared with the routinely used cell homogenates or purified membrane fractions. In this study, a real-time NanoBRET-based binding assay was established and validated to detect binding of unlabeled ligands to the histamine H3 receptor (H3R) and histamine H4 receptor on intact cells. Obtained residence times of clinically tested H3R antagonists were reflected by their duration of H3R antagonism in a functional receptor recovery assay.
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Affiliation(s)
- Tamara A M Mocking
- Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Eléonore W E Verweij
- Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Henry F Vischer
- Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Rob Leurs
- Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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23
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Watanabe M, Kobayashi T, Ito Y, Fukuda H, Yamada S, Arisawa M, Shuto S. Design and synthesis of histamine H 3/H 4 receptor ligands with a cyclopropane scaffold. Bioorg Med Chem Lett 2018; 28:3630-3633. [PMID: 30385161 DOI: 10.1016/j.bmcl.2018.10.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/19/2018] [Accepted: 10/24/2018] [Indexed: 12/27/2022]
Abstract
We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3/H4 antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H3/H4 ligands in the H4 receptor can be different from those of the indole/benzimidazole-piperazine derivatives.
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Affiliation(s)
- Mizuki Watanabe
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
| | - Takaaki Kobayashi
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Yoshihiko Ito
- Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Hayato Fukuda
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Shizuo Yamada
- Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Mitsuhiro Arisawa
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Satoshi Shuto
- Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
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A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction. Tetrahedron Lett 2018. [DOI: 10.1016/j.tetlet.2018.09.039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Ko K, Kim HJ, Ho PS, Lee SO, Lee JE, Min CR, Kim YC, Yoon JH, Park EJ, Kwon YJ, Yun JH, Yoon DO, Kim JS, Park WS, Oh SS, Song YM, Cho WK, Morikawa K, Lee KJ, Park CH. Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis. J Med Chem 2018; 61:2949-2961. [PMID: 29579390 DOI: 10.1021/acs.jmedchem.7b01855] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets. A pharmacophore-based virtual screening system constructed in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently led us to discover pyrido[2,3- e]tetrazolo[1,5- a]pyrazine analogue 48 as a novel chemotype of a potent and highly selective H4R antagonist. Importantly, orally administered compound 48 exhibits remarkable efficacy on antipruritus and anti-inflammation with a favorable pharmacokinetic (PK) profile in several mouse models of AD. Thus, these data strongly suggest that our compound 48 is a promising clinical candidate for treatment of AD.
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Affiliation(s)
- Kwangseok Ko
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Hye-Jung Kim
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Pil-Su Ho
- JW Pharmaceutical Co., Ltd ., 2477, Nambusunhwan-ro, Seocho-gu , Seoul , 06725 , Korea
| | - Soon Ok Lee
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Ji-Eun Lee
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Cho-Rong Min
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Yu Chul Kim
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Ju-Han Yoon
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Eun-Jung Park
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Young-Jin Kwon
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Jee-Hun Yun
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Dong-Oh Yoon
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Jung-Sook Kim
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Woul-Seong Park
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Seung-Su Oh
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Yu-Mi Song
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Woon-Ki Cho
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
| | - Kazumi Morikawa
- Chugai Pharmaceutical Co., Ltd., Fuji Gotemba Research Laboratories , 1-135 Komakado, Gotemba , Shizuoka , 412-8513 , Japan
| | - Kyoung-June Lee
- JW Pharmaceutical Co., Ltd ., 2477, Nambusunhwan-ro, Seocho-gu , Seoul , 06725 , Korea
| | - Chan-Hee Park
- C&C Research Laboratories, DRC, Sungkyunkwan University , 2066, Seobu-ro, Jangan-gu, Suwon-si , Gyeonggi-do , 16419 , Korea
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Thurmond RL, Venable J, Savall B, La D, Snook S, Dunford PJ, Edwards JP. Clinical Development of Histamine H 4 Receptor Antagonists. Handb Exp Pharmacol 2017; 241:301-320. [PMID: 28233185 DOI: 10.1007/164_2016_130] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The discovery of the histamine H4 receptor (H4R) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H4R relative to other histamine receptors. The discovery of the selective H4R antagonist JNJ 7777120 was vital for showing a role for the H4R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective H4R antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another H4R antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many H4R antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that H4R antagonists can be beneficial in treating atopic dermatitis and pruritus.
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Affiliation(s)
| | | | - Brad Savall
- Janssen Research & Development, LLC, San Diego, CA, 92121, USA
| | - David La
- Janssen Research & Development, LLC, San Diego, CA, 92121, USA
| | - Sandra Snook
- Janssen Research & Development, LLC, San Diego, CA, 92121, USA
| | - Paul J Dunford
- Janssen Research & Development, LLC, San Diego, CA, 92121, USA
| | - James P Edwards
- Janssen Research & Development, LLC, San Diego, CA, 92121, USA
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Abstract
Histamine is a pro-inflammatory mediator with a prominent role in allergic diseases. Antagonists at the histamine receptor subtype 1 are central in anti-allergic therapies, with the exception of allergic asthma, where they are clinically without effect. The latest identified histamine receptor subtype 4, which is expressed mainly in hematopoietic cells, now provides a reasonable target for new therapeutic strategies inhibiting histamine function. The pathophysiology of allergy, esp. allergic asthma, and in its context the effects of antagonists at the histamine receptor subtype 4 in preclinical and clinical settings are discussed in this chapter.
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Nagarajan G, Mariappanadar V, Tamizh M, Kaliappan I, Elden BT. Effect of H4R antagonist N-(2-aminoethyl)-5-chloro-1H-indol-2-carboxamides and 5-chloro-2-(piperazin-1-ylmethyl)-1H-benzimidazole on histamine and 4-methylhistamine-induced mast cell response. J Recept Signal Transduct Res 2016; 37:304-313. [DOI: 10.1080/10799893.2016.1247863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Gomathi Nagarajan
- Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Tamil Nadu, India
| | - Vairamani Mariappanadar
- Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Tamil Nadu, India
| | - Muthu Tamizh
- Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM University, Kattankulathur, Tamil Nadu, India
| | - Ilango Kaliappan
- Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM University, Kattankulathur, Tamil Nadu, India
| | - Berla Thangam Elden
- Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Tamil Nadu, India
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Gangwar RS, Landolina N, Arpinati L, Levi-Schaffer F. Mast cell and eosinophil surface receptors as targets for anti-allergic therapy. Pharmacol Ther 2016; 170:37-63. [PMID: 27773785 DOI: 10.1016/j.pharmthera.2016.10.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Roopesh Singh Gangwar
- Pharmacology & Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Nadine Landolina
- Pharmacology & Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Ludovica Arpinati
- Pharmacology & Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Francesca Levi-Schaffer
- Pharmacology & Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
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30
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Mogilski S, Kubacka M, Łażewska D, Więcek M, Głuch-Lutwin M, Tyszka-Czochara M, Bukowska-Strakova K, Filipek B, Kieć-Kononowicz K. Aryl-1,3,5-triazine ligands of histamine H 4 receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide. Inflamm Res 2016; 66:79-95. [PMID: 27766379 PMCID: PMC5209447 DOI: 10.1007/s00011-016-0997-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 10/06/2016] [Accepted: 10/11/2016] [Indexed: 12/30/2022] Open
Abstract
Objective and design Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity. Materials and subjects We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. Treatments In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 µM. Methods We examined anti-inflammatory and analgesic effects of the new H4R antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine H1 receptor in functional studies. Results Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenan-induced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as TNFα and IL-1β. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H1 receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. Conclusions Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily H4R–dependent.
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Affiliation(s)
- Szczepan Mogilski
- Departament of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
| | - Monika Kubacka
- Departament of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Dorota Łażewska
- Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Małgorzata Więcek
- Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Monika Głuch-Lutwin
- Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland
| | - Małgorzata Tyszka-Czochara
- Department of Radioligands, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Karolina Bukowska-Strakova
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.,Department of Clinical Immunology and Transplantology, Polish-American Institute of Pediatrics, Medical College, Jagiellonian University, Krakow, Poland
| | - Barbara Filipek
- Departament of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Katarzyna Kieć-Kononowicz
- Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
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31
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Levoin N, Labeeuw O, Billot X, Calmels T, Danvy D, Krief S, Berrebi-Bertrand I, Lecomte JM, Schwartz JC, Capet M. Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening. Eur J Med Chem 2016; 125:565-572. [PMID: 27718472 DOI: 10.1016/j.ejmech.2016.09.074] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 09/21/2016] [Accepted: 09/22/2016] [Indexed: 12/29/2022]
Abstract
The involvement of histamine H4 receptor (H4R) in immune cells chemotaxis and mediator release makes it an attractive target for the treatment of inflammation disorders. A decade of medicinal chemistry efforts has led to several promising ligands, although the chemical structures described so far possesses a singular limited diversity. We report here the discovery of novel structures, belonging to completely different scaffolds. The virtual screening was planed as a two-steps process. First, using a "scout screening" methodology, we have experimentally probed the H4R ligand binding site using a small size chemical library with very diverse structures, and identified a hit that further assist us in refining a raw 3D homology model. Second, the refined 3D model was used to conduct a widened virtual screening. This two-steps strategy proved to be very successful, both in terms of structural diversity and hit rate (23%). Moreover, the hits have high affinity for the H4R, with most potent ligands in the nanomolar range.
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Affiliation(s)
- Nicolas Levoin
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France.
| | - Olivier Labeeuw
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
| | - Xavier Billot
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
| | - Thierry Calmels
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
| | - Denis Danvy
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
| | - Stéphane Krief
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
| | | | - Jeanne-Marie Lecomte
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
| | | | - Marc Capet
- Bioprojet-Biotech, 4rue du Chesnay Beauregard, 35762 Saint-Gregoire Cedex, France
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Kaneko H, Ye F, Ijima R, Kachi S, Kato S, Nagaya M, Higuchi A, Terasaki H. Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular degeneration. Br J Pharmacol 2016; 171:3754-63. [PMID: 24787705 DOI: 10.1111/bph.12737] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 04/03/2014] [Accepted: 04/11/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND PURPOSE The present treatment for choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) is not sufficient. Hence, we examined the therapeutic efficacy of reducing histamine H4 receptor expression on CNV in mice. EXPERIMENTAL APPROACH H4 receptor expression was examined in CNVs from patients with AMD. In mice, laser photocoagulation was performed in the retina to induce experimental CNV (laser CNV). Protein and mRNA expression levels were determined and CNV volume measured in wild-type and Hrh4(-/-) mice with laser CNV. The effects of JNJ7777120, an H4 receptor antagonist, administered intravitreously, on CNV volume and pathological vessel leakage were determined in mice with laser CNV and controls. Fundus imaging, retinal histology and electroretinography were performed on eyes injected with JNJ7777120 to evaluate retinal toxicity. KEY RESULTS Human H4 receptors were only confirmed in CNV samples from AMD patients and not in the other subretinal tissues. Mouse H4 receptors were expressed in retinal pigment epithelium only after inducing laser CNV in wild-type mice, and were co-localized with the macrophage marker F4/80. Laser CNV volume was reduced in Hrh4(-/-) mice compared with that in wild-type mice, and JNJ7777120 suppressed laser-induced CNV volume and pathological CNV leakage in wild-type mice. Also eyes injected with JNJ7777120 did not show retinal degeneration. CONCLUSIONS AND IMPLICATIONS H4 receptors are expressed in macrophages that accumulate around CNVs. Suppressing H4 receptor expression prevented the pathological vessel leakage without showing retinal toxicity, indicating that the H4 receptor has potential as a novel therapeutic target in AMD.
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Affiliation(s)
- Hiroki Kaneko
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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33
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Pontiki E, Hadjipavlou-Litina D. QSAR models on H4 receptor antagonists associated with inflammation and anaphylaxis. J Biomol Struct Dyn 2016; 35:968-1005. [DOI: 10.1080/07391102.2016.1166986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Eleni Pontiki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki , Thessaloniki 54124, Greece
| | - Dimitra Hadjipavlou-Litina
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki , Thessaloniki 54124, Greece
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Geyer R, Nordemann U, Strasser A, Wittmann HJ, Buschauer A. Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists. J Med Chem 2016; 59:3452-70. [PMID: 27007611 DOI: 10.1021/acs.jmedchem.6b00120] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers.
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Affiliation(s)
- Roland Geyer
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany
| | - Uwe Nordemann
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany
| | - Andrea Strasser
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany
| | - Hans-Joachim Wittmann
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany
| | - Armin Buschauer
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany
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Grosicki M, Wójcik T, Chlopicki S, Kieć-Kononowicz K. In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium. Eur J Pharmacol 2016; 777:49-59. [PMID: 26939881 DOI: 10.1016/j.ejphar.2016.02.061] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 02/25/2016] [Accepted: 02/26/2016] [Indexed: 01/08/2023]
Abstract
It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium.
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Affiliation(s)
- Marek Grosicki
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Krakow, Poland; Jagiellonian Center for Experimental Therapeutics (JCET), Bobrzyńskiego 14, 30-348, Krakow, Poland
| | - Tomasz Wójcik
- Jagiellonian Center for Experimental Therapeutics (JCET), Bobrzyńskiego 14, 30-348, Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Center for Experimental Therapeutics (JCET), Bobrzyńskiego 14, 30-348, Krakow, Poland; Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, 31-531, Krakow, Poland
| | - Katarzyna Kieć-Kononowicz
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688 Krakow, Poland.
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36
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Hammer SG, Gobleder S, Naporra F, Wittmann HJ, Elz S, Heinrich MR, Strasser A. 2,4-Diaminopyrimidines as dual ligands at the histamine H1 and H4 receptor-H1/H4-receptor selectivity. Bioorg Med Chem Lett 2015; 26:292-300. [PMID: 26718844 DOI: 10.1016/j.bmcl.2015.12.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 12/10/2015] [Accepted: 12/10/2015] [Indexed: 11/20/2022]
Abstract
Distinct diaminopyrimidines, for example, 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine are histamine H4 receptor (H4R) antagonists and show high affinity to the H4R, but only a moderate affinity to the histamine H1 receptor (H1R). Within previous studies it was shown that an aromatic side chain with a distinct distance to the basic amine and aromatic core is necessary for affinity to the human H1R (hH1R). Thus, a rigid aminopyrimidine with a tricyclic core was used as a lead structure. There, (1) the flexible aromatic side chain was introduced, (2) the substitution pattern of the pyrimidine core was exchanged and (3) rigidity was decreased by opening the tricyclic core. Within the present study, two compounds with similar affinity in the one digit μM range to the human H1R and H4R were identified. While the affinity at the hH1R increased about 4- to 8-fold compared to the parent diaminopyrimidine, the affinity to the hH4R decreased about 5- to 8-fold. In addition to the parent diaminopyrimidine, two selected compounds were docked into the H1R and H4R and molecular dynamic studies were performed to predict the binding mode and explain the experimental results on a molecular level. The two new compounds may be good lead structures for the development of dual H1/H4 receptor ligands with affinities in the same range.
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Affiliation(s)
- Sebastian G Hammer
- Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, D-91052 Erlangen, Germany
| | - Susanne Gobleder
- Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
| | - Franziska Naporra
- Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
| | - Hans-Joachim Wittmann
- Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
| | - Sigurd Elz
- Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany
| | - Markus R Heinrich
- Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, D-91052 Erlangen, Germany.
| | - Andrea Strasser
- Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany.
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Sadek B, Stark H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 2015; 106:56-73. [PMID: 26581501 DOI: 10.1016/j.neuropharm.2015.11.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 11/05/2015] [Accepted: 11/06/2015] [Indexed: 12/17/2022]
Abstract
Histamine, a biogenic amine, is considered as a principle mediator of multiple physiological effects through binding to its H1, H2, H3, and H4 receptors (H1-H4Rs). Currently, the HRs have gained attention as important targets for the treatment of several diseases and disorders ranging from allergy to Alzheimer's disease and immune deficiency. Accordingly, medicinal chemistry studies exploring histamine-like molecules and their physicochemical properties by binding and interacting with the four HRs has led to the development of a diversity of agonists and antagonists that display selectivity for each HR subtype. An overview on H1-R4Rs and developed ligands representing some key steps in development is provided here combined with a short description of structure-activity relationships for each class. Main chemical diversities, pharmacophores, and pharmacological profiles of most innovative H1-H4R agonists and antagonists are highlighted. Therefore, this overview should support the rational choice for the optimal ligand selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies. This article is part of the Special Issue entitled 'Histamine Receptors'.
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Affiliation(s)
- Bassem Sadek
- Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates.
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitaetsstr. 1, 40225 Düsseldorf, Germany
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Ahmad SF, Zoheir KMA, Ansari MA, Nadeem A, Bakheet SA, Al-Hoshani AR, Al-Shabanah OA, Al-Harbi MM, Attia SM. Histamine 4 receptor promotes expression of costimulatory B7.1/B7.2 molecules, CD28 signaling and cytokine production in stress-induced immune responses. J Neuroimmunol 2015; 289:30-42. [PMID: 26616869 DOI: 10.1016/j.jneuroim.2015.10.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/11/2015] [Accepted: 10/13/2015] [Indexed: 01/01/2023]
Abstract
Recently, the expression of histamine 4 receptor (H4R) on neurons was reported, however its function in cells within the central nervous system (CNS) remains poorly understood. To this end, we used the H4R agonist, 4-methylhistamine (4-MeH), and the H4R antagonist, JNJ77777120 (JNJ), to investigate the function of H4R signaling in immune cells in a murine model of chronic stress. Treatment of stressed mice with 4-MeH resulted in an increase in the proportion of lymphocyte subsets (CD3(+), CD8(+), CD28(+), and CD4(+)CD28(+)) and cells expressing the co-stimulatory molecules CD80(+) (B7.1) and CD86(+) (B7.2) in heparinized blood as compared to normal control (NC) and stressed control (SC) groups. We also observed that as compared to NC and SC mice, 4-MeH-treated mice showed greater production of IL-2(+), IL-6(+), IL-9(+), IL-21(+), and IL-27(+) cytokines in the spleen and by splenic CD4(+) T cells. Furthermore, 4-MeH treatment of stressed mice led to an increase in the levels of serum Th1/Th17 cytokines and corticosterone, and a decrease in Th2 cytokines. Treatment of chronically-stressed mice with 4-MeH also augmented expression of IL-6, IL-21, NF-κB p65, and STAT3 mRNA. Moreover, Western blot analyses confirmed increased protein expression of NF-κB, iNOS, and STAT3 expression following 4-MeH treatment of chronically-stressed mice as compared to controls. These proteins provide a novel relevant targets for the manipulation of chronic stress induced immune regulation. In striking contrast, treatment of stressed mice with the H4R antagonist, JNJ, resulted in a substantial reduction in all of the aforementioned effects upon immune cell percentages and cytokine production.
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Affiliation(s)
- Sheikh Fayaz Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
| | - Khairy M A Zoheir
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cairo, Egypt
| | - Mushtaq Ahmad Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Nadeem
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ali R Al-Hoshani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Othman A Al-Shabanah
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed M Al-Harbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sabry M Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt
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Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K. (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands. Eur J Med Chem 2015; 103:238-51. [DOI: 10.1016/j.ejmech.2015.08.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 08/03/2015] [Accepted: 08/06/2015] [Indexed: 01/29/2023]
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Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WLS, Stark H, Thurmond RL, Haas HL. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacol Rev 2015; 67:601-55. [PMID: 26084539 PMCID: PMC4485016 DOI: 10.1124/pr.114.010249] [Citation(s) in RCA: 393] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.
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Affiliation(s)
- Pertti Panula
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Paul L Chazot
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Marlon Cowart
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Ralf Gutzmer
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Rob Leurs
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Wai L S Liu
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Holger Stark
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Robin L Thurmond
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
| | - Helmut L Haas
- Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry and Institute of Neurophysiology, Medical Faculty, Westfalische-Wilhelms-University, Muenster, Germany (H.L.H.); Heinrich-Heine-University Duesseldorf, Germany (H.S.); and Janssen Research & Development, LLC, San Diego, California (R.L.T.)
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Tichenor MS, Thurmond RL, Venable JD, Savall BM. Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators. J Med Chem 2015; 58:7119-27. [PMID: 25993395 DOI: 10.1021/acs.jmedchem.5b00516] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.
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Affiliation(s)
- Mark S Tichenor
- Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States
| | - Robin L Thurmond
- Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States
| | - Jennifer D Venable
- Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States
| | - Brad M Savall
- Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States
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Thurmond RL. The histamine H4 receptor: from orphan to the clinic. Front Pharmacol 2015; 6:65. [PMID: 25873897 PMCID: PMC4379874 DOI: 10.3389/fphar.2015.00065] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 03/12/2015] [Indexed: 01/10/2023] Open
Abstract
The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans.
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Wifling D, Löffel K, Nordemann U, Strasser A, Bernhardt G, Dove S, Seifert R, Buschauer A. Molecular determinants for the high constitutive activity of the human histamine H4 receptor: functional studies on orthologues and mutants. Br J Pharmacol 2015; 172:785-98. [PMID: 24903527 PMCID: PMC4301689 DOI: 10.1111/bph.12801] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 05/19/2014] [Accepted: 05/27/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE Some histamine H4 receptor ligands act as inverse agonists at the human H4 receptor (hH4 R), a receptor with exceptionally high constitutive activity, but as neutral antagonists or partial agonists at the constitutively inactive mouse H4 receptor (mH4 R) and rat H4 receptor (rH4 R). To study molecular determinants of constitutive activity, H4 receptor reciprocal mutants were constructed: single mutants: hH4 R-F169V, mH4 R-V171F, hH4 R-S179A, hH4 R-S179M; double mutants: hH4 R-F169V+S179A, hH4 R-F169V+S179M and mH4 R-V171F+M181S. EXPERIMENTAL APPROACH Site-directed mutagenesis with pVL1392 plasmids containing hH4 or mH4 receptors were performed. Wild-type or mutant receptors were co-expressed with Gαi2 and Gβ1 γ2 in Sf9 cells. Membranes were studied in saturation and competition binding assays ([(3) H]-histamine), and in functional [(35) S]-GTPγS assays with inverse, partial and full agonists of the hH4 receptor. KEY RESULTS Constitutive activity decreased from the hH4 receptor via the hH4 R-F169V mutant to the hH4 R-F169V+S179A and hH4 R-F169V+S179M double mutants. F169 alone or in concert with S179 plays a major role in stabilizing a ligand-free active state of the hH4 receptor. Partial inverse hH4 receptor agonists like JNJ7777120 behaved as neutral antagonists or partial agonists at species orthologues with lower or no constitutive activity. Some partial and full hH4 receptor agonists showed decreased maximal effects and potencies at hH4 R-F169V and double mutants. However, the mutation of S179 in the hH4 receptor to M as in mH4 receptor or A as in rH4 receptor did not significantly reduce constitutive activity. CONCLUSIONS AND IMPLICATIONS F169 and S179 are key amino acids for the high constitutive activity of hH4 receptors and may also be of relevance for other constitutively active GPCRs. LINKED ARTICLES This article is part of a themed issue on Histamine Pharmacology Update published in volume 170 issue 1. To view the other articles in this issue visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2013.170.issue-1/issuetoc.
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Affiliation(s)
- D Wifling
- Institute of Pharmacy, University of Regensburg, Regensburg, Germany
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Savall BM, Meduna SP, Tays K, Cai H, Thurmond RL, McGovern P, Gaul M, Zhao BP, Edwards JP. Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators. Bioorg Med Chem Lett 2015; 25:956-9. [DOI: 10.1016/j.bmcl.2014.12.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 12/08/2014] [Accepted: 12/09/2014] [Indexed: 10/24/2022]
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Wifling D, Bernhardt G, Dove S, Buschauer A. The extracellular loop 2 (ECL2) of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity. PLoS One 2015; 10:e0117185. [PMID: 25629160 PMCID: PMC4309601 DOI: 10.1371/journal.pone.0117185] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 12/21/2014] [Indexed: 11/25/2022] Open
Abstract
In contrast to the corresponding mouse and rat orthologs, the human histamine H4 receptor (hH4R) shows extraordinarily high constitutive activity. In the extracellular loop (ECL), replacement of F169 by V as in the mouse H4R significantly reduced constitutive activity. Stabilization of the inactive state was even more pronounced for a double mutant, in which, in addition to F169V, S179 in the ligand binding site was replaced by M. To study the role of the FF motif in ECL2, we generated the hH4R-F168A mutant. The receptor was co-expressed in Sf9 insect cells with the G-protein subunits Gαi2 and Gβ1γ2, and the membranes were studied in [3H]histamine binding and functional [35S]GTPγS assays. The potency of various ligands at the hH4R-F168A mutant decreased compared to the wild-type hH4R, for example by 30- and more than 100-fold in case of the H4R agonist UR-PI376 and histamine, respectively. The high constitutive activity of the hH4R was completely lost in the hH4R-F168A mutant, as reflected by neutral antagonism of thioperamide, a full inverse agonist at the wild-type hH4R. By analogy, JNJ7777120 was a partial inverse agonist at the hH4R, but a partial agonist at the hH4R-F168A mutant, again demonstrating the decrease in constitutive activity due to F168A mutation. Thus, F168 was proven to play a key role not only in ligand binding and potency, but also in the high constitutive activity of the hH4R.
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Affiliation(s)
- David Wifling
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany
| | - Günther Bernhardt
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany
| | - Stefan Dove
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany
| | - Armin Buschauer
- Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany
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Istyastono EP, Kooistra AJ, Vischer HF, Kuijer M, Roumen L, Nijmeijer S, Smits RA, de Esch IJP, Leurs R, de Graaf C. Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4 receptor. MEDCHEMCOMM 2015. [DOI: 10.1039/c5md00022j] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Structure-based virtual screening using H1R- and β2R-based histamine H4R homology models identified 9 fragments with an affinity ranging from 0.14 to 6.3 μm for H4R.
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Affiliation(s)
- Enade P. Istyastono
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Albert J. Kooistra
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Henry F. Vischer
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Martien Kuijer
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Luc Roumen
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Saskia Nijmeijer
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | | | - Iwan J. P. de Esch
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Rob Leurs
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
| | - Chris de Graaf
- Division of Medicinal Chemistry
- Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)
- Faculty of Exact Sciences
- VU University Amsterdam
- 1081 HV Amsterdam
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Savall BM, Meduna SP, Venable J, Wei J, Smith RC, Hack MD, Thurmond RL, McGovern P, Edwards JP. The effect of pKa on pyrimidine/pyridine-derived histamine H4 ligands. Bioorg Med Chem Lett 2014; 24:5489-92. [DOI: 10.1016/j.bmcl.2014.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 09/26/2014] [Accepted: 10/01/2014] [Indexed: 12/01/2022]
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Corrêa MF, dos Santos Fernandes JP. Histamine H4 receptor ligands: future applications and state of art. Chem Biol Drug Des 2014; 85:461-80. [PMID: 25228262 DOI: 10.1111/cbdd.12431] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.
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Affiliation(s)
- Michelle Fidelis Corrêa
- Departamento de Ciências Exatas e da Terra, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, UNIFESP, Diadema, Brazil
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Pappalardo M, Shachaf N, Basile L, Milardi D, Zeidan M, Raiyn J, Guccione S, Rayan A. Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism. PLoS One 2014; 9:e109340. [PMID: 25330207 PMCID: PMC4199621 DOI: 10.1371/journal.pone.0109340] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 09/10/2014] [Indexed: 02/03/2023] Open
Abstract
The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner.
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Affiliation(s)
- Matteo Pappalardo
- Department of Chemical Sciences, University of Catania, Catania, Italy
| | - Nir Shachaf
- Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel
| | - Livia Basile
- Etnalead s.r.l., Scuola Superiore di Catania, University of Catania, Catania, Italy
| | - Danilo Milardi
- National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy
| | - Mouhammed Zeidan
- Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel
| | - Jamal Raiyn
- Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel
| | - Salvatore Guccione
- Etnalead s.r.l., Scuola Superiore di Catania, University of Catania, Catania, Italy
- Department of Pharmaceutical Sciences, University of Catania, Catania, Italy
| | - Anwar Rayan
- Drug Discovery Informatics Lab, QRC-Qasemi Research Center, Al-Qasemi Academic College, Baka El-Garbiah, Israel
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Feliszek M, Speckmann V, Schacht D, von Lehe M, Stark H, Schlicker E. A search for functional histamine H4 receptors in the human, guinea pig and mouse brain. Naunyn Schmiedebergs Arch Pharmacol 2014; 388:11-7. [PMID: 25300787 DOI: 10.1007/s00210-014-1053-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 09/28/2014] [Indexed: 01/08/2023]
Abstract
Histamine H4 receptors are expressed in immune cells, but their potential role in the brain is less clear. Although H4 transcripts have been identified in human and rat brain, the presence of H4 receptors on the protein level has so far not been proven since appropriate antibodies fulfilling the strict criteria for G protein-coupled receptors are missing. Here, we searched for functional H4 receptors in human, guinea pig and mouse cortex. We studied whether H4 receptor activation is associated with increased GTPγS binding and reduced noradrenaline release. The latter two effects have been previously shown for H3 receptors, which, like the H4 receptors, are coupled to G i/o protein. G protein activation was studied using (35)S-GTPγS binding in cortical membranes. The electrically induced (3)H-noradrenaline release was determined in superfused cortical slices. The H4 agonist 4-methylhistamine failed to affect (35)S-GTPγS binding and/or noradrenaline release in human, guinea pig and mouse cortex although an H 3 receptor-mediated increase in (35)S-GTPγS binding and inhibition of noradrenaline release occurred in parallel experiments. In conclusion, functional H4 receptors increasing (35)S-GTPγS binding and/or decreasing noradrenaline release are not found in human, guinea pig and mouse cortex.
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Affiliation(s)
- Monika Feliszek
- Institut für Pharmakologie und Toxikologie, Universität Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany
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