Opportunities and challenges for the development of M muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits.

Targeting allosteric sites of M muscarinic acetylcholine receptors (M receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M receptor. This has led to the identification of a structurally diverse range of highly selective M PAMs. In preclinical models, M PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M PAMs have reached early-stage clinical trials, with many of them failing to progress further due to on-target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M PAMs from bench-side to bedside. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.