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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Pharmacol. Mar 9, 2016; 5(1): 32-43
Published online Mar 9, 2016. doi: 10.5497/wjp.v5.i1.32
Allosteric modulation of cholinergic system: Potential approach to treating cognitive deficits of schizophrenia
Shaun Hopper, Madhara Udawela, Elizabeth Scarr, Brian Dean
Shaun Hopper, Madhara Udawela, Elizabeth Scarr, Brian Dean, the Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Melbourne, Victoria 3052, Australia
Elizabeth Scarr, Brian Dean, Department of Psychiatry, the University of Melbourne, Melbourne, Victoria 3052, Australia
Author contributions: Hopper S, Udawela M, Scarr E and Dean B contributed to this paper.
Conflict-of-interest statement: There are no competing financial interests in relation to the work described in this paper. The authors report no competing interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Shaun Hopper, MSc, the Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Gate 11 Royal Parade, Melbourne, Victoria 3052, Australia. shaun.hopper@florey.edu.au
Telephone: +61-90-356475
Received: September 19, 2015
Peer-review started: September 22, 2015
First decision: October 30, 2015
Revised: November 26, 2015
Accepted: December 29, 2015
Article in press: January 4, 2016
Published online: March 9, 2016
Processing time: 166 Days and 23.3 Hours
Abstract

Schizophrenia is a psychiatric disorder affecting approximately 1% of the population worldwide and is characterised by the presence of positive and negative symptoms and cognitive deficits. Whilst current therapeutics ameliorate positive symptoms, they are largely ineffective in improving negative symptoms and cognitive deficits. The cholinergic neurotransmitter system heavily influences cognitive function and there is evidence that implicates disruption of the central cholinergic system in schizophrenia. Historically, targeting the cholinergic system has been impeded by poor selectivity leading to intolerable side effects warranting the need to develop more targeted therapeutic compounds. In this review we will summarise evidence supporting the roles of the cholinergic system, particularly the muscarinic M1 receptor, in the pathophysiology of schizophrenia and discuss the potential of a promising new class of candidate compounds, allosteric ligands, for addressing the difficulties involved in targeting this system. The body of evidence presented here highlights the dysfunction of the cholinergic system in schizophrenia and that targeting this system by taking advantage of allosteric ligands is having clinically meaningful effect on cognitive deficits.

Keywords: Central nervous system; Antipsychotic; Allosteric; Cholinergic; Schizophrenia; Mutagenesis; Cognition; Muscarinic

Core tip: Schizophrenia is a psychiatric disorder affecting approximately 1% of the world population. Current treatments inadequately redress the cognitive impairments associated with the disease. In light of that we discuss the role of the cholinergic system, in particular the muscarinic M1 receptor, in schizophrenia and cognition and how allosteric compounds are being developed to address this undertreated aspect of the disease. We also discuss and compile mutagenesis studies of the muscarinic M1 receptor and how they relate to allosteric binding and function.