Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders

Trends Pharmacol Sci. 2019 Dec;40(12):1006-1020. doi: 10.1016/j.tips.2019.10.007. Epub 2019 Nov 8.

Abstract

Muscarinic acetylcholine receptors (mAChR) play important roles in regulating complex behaviors such as cognition, movement, and reward, making them ideally situated as potential drug targets for the treatment of several brain disorders. Recent advances in the discovery of subtype-selective allosteric modulators for mAChRs has provided an unprecedented opportunity for highly specific modulation of signaling by individual mAChR subtypes in the brain. Recently, mAChR allosteric modulators have entered clinical development for Alzheimer's disease (AD) and schizophrenia, and have potential utility for other brain disorders. However, mAChR allosteric modulators can display a diverse array of pharmacological properties, and a more nuanced understanding of the mAChR will be necessary to best translate preclinical findings into successful clinical treatments.

Keywords: NAM; PAM; allosteric modulator; muscarinic acetylcholine receptor; neurological disorder; signal bias.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Clinical Trials as Topic
  • Humans
  • Mental Disorders / drug therapy*
  • Mental Disorders / metabolism
  • Molecular Targeted Therapy
  • Muscarinic Agonists / pharmacology*
  • Muscarinic Agonists / therapeutic use
  • Muscarinic Antagonists / pharmacology*
  • Muscarinic Antagonists / therapeutic use
  • Nervous System Diseases / drug therapy*
  • Nervous System Diseases / metabolism
  • Receptors, Muscarinic / metabolism*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism

Substances

  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Receptors, Muscarinic