The Prosperity and Adversity of M4 Muscarinic Acetylcholine Receptor Activators in the Treatment of Neuropsychiatric Disorders

Abstract

Since the serendipitous discovery of chlorpromazine in the 1950s, almost all current anti-schizophrenia drugs utilize the same mode of action by blocking the dopamine receptors in the brain. Unfortunately, these only treat part of the symptoms and are ineffective in almost 30% of patients. The recent FDA approval of Cobenfy, a coformulation of xanomeline, a M₁/M₄ muscarinic acetylcholine receptor (mAChR) agonist, and a peripherally restricted pan-mAChR blocker, has propelled the M₄R as a validated and novel antipsychotic target. With >25 years of history in developing xanomeline, significant challenges remain in developing M₄R activators, either at the ACh orthosteric binding site or allosterically via secondary less-conserved binding sites. Herein, we summarize recent successes and failures of M₄R agonists and positive allosteric modulators, along with the progress in structure-activity relationship studies on both orthosteric and allosteric scaffolds to offer pathways for future therapeutics to this novel biological target for neuropsychiatric disorders.