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

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.

• Publication year

  2025

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2025-04-16

• Fields of study

  Medicine, Psychology

• Identifiers
  DOI 10.1021/acs.jmedchem.5c00678PMID 40237346
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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