Biased M1-muscarinic receptor mutant mice inform design of next generation drugs

Cholinesterase inhibitors, the current frontline symptomatic treatmentfor Alzheimer’s disease(AD), are associated with low efficacy and adverseeffects. M1 muscarinic acetylcholine receptors(M1 mAChRs)represent a potential alternativetherapeutic target;however,drug discovery programmes focused on thisG protein-coupled receptor (GPCR) have failed largely due tocholinergic adverse responses.Employing novelchemogeneticand phosphorylation-deficient, G protein-biased,mouse models, paired with a tool-box of probe molecules, weestablishpreviously unappreciatedpharmacologically targetableM1 mAChR neurological processes,including anxiety-like behaviours and hyper-locomotion. By mapping the upstream signalling pathways regulating these responses,we determine the importance of receptor phosphorylation-dependent signalling in driving clinically relevant outcomes and in controlling adverse effects including “epileptic-like”seizures. Weconclude thatM1 mAChRligands that promotereceptor-phosphorylation dependent signalling would protect against cholinergic-adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behaviour relevant for the treatment of AD.