Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic

• Published in: Trends in pharmacological sciences (Regular ed.) 2022-12, Vol.43 (12), p.1098-1112
• Main Authors: Yohn, Samantha E., Weiden, Peter W., Felder, Christian C., Stahl, Stephen M.
• Format: Article
• Language: English
• Subjects: Acetylcholine; Humans; mAChR; muscarinic; Muscarinic Agonists - pharmacology; Muscarinic Agonists - therapeutic use; psychosis; Psychotic Disorders - drug therapy; Receptor, Muscarinic M1 - agonists; Receptors, Muscarinic; schizophrenia; Schizophrenia - drug therapy; xanomeline
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2022.09.006

Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia. Effective control of psychotic (positive) symptoms is key to successful drug development targets for schizophrenia.Central mAChR agonists have shown antipsychotic activity without any direct dopamine receptor antagonism.Early attempts at developing mAChR agonists targeting psychosis were thwarted by tolerability problems from unwanted peripheral mAChR receptor activation, but recent advances aim to reduce tolerability burden.M1 and M4 receptors are the subtypes most closely linked to antipsychotic activity targets and current mAChR agonists targeting psychosis include those with central M1, M4, or dual M1/M4 receptor agonist properties.Strategies to minimize peripheral muscarinic adverse events include (i) using orthosteric, allosteric, or bitopic functionality strategies, and (ii) using a cotreatment with a peripheral muscarinic antagonist.