Opportunities and challenges for the development of M₁ muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits

Targeting allosteric sites of M₁ muscarinic acetylcholine receptors (M₁ 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 M₁ receptor. This has led to the identification of a structurally diverse range of highly selective M₁ PAMs. In preclinical models, M₁ PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M₁ 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 M₁ receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M₁ PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M₁ PAMs from bench-side to bedside.