Design, synthesis, and pharmacological evaluation of novel M muscarinic receptor positive allosteric modulators for schizophrenia treatment.

The muscarinic acetylcholine M receptor (M mAChR) has emerged as a promising target for schizophrenia treatment. M positive allosteric modulators (PAMs) can enhance endogenous acetylcholine signaling by binding to the allosteric site of the receptor. Compared with M agonists, the regulation of M mAChR function by PAMs is more precise and has fewer off-target effects. M PAMs under research have demonstrated excellent subtype selectivity and favorable safety profiles, but their efficacy has been limited in clinical trials. To improve the therapeutic efficacy, a series of novel M PAMs containing a biphenyl scaffold were designed and synthesized based on the existing M PAM structures. Among them, compound A9 (EC = 513 nM) demonstrated promising M mAChR selectivity, PAM activity, and favorable pharmacokinetic properties. Moreover, in the mice hyperactivity model, A9 reversed MK-801-induced hyperlocomotion (ED = 20.04 mg/kg, p.o.). These findings provide a scientific basis for the rational design of novel M4 PAMs with optimized pharmacological profiles and enhanced therapeutic potential for better schizophrenia treatment.