Classics in Chemical Neuroscience: Xanomeline

ACS Chem Neurosci. 2017 Mar 15;8(3):435-443. doi: 10.1021/acschemneuro.7b00001. Epub 2017 Feb 13.

Abstract

Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer's disease (AD) patients. Despite the compound's promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound's unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1 or M4. This Review will address xanomeline's overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.

Keywords: Alzheimer’s disease; Xanomeline; allosteric modulation; antipsychotic; muscarinic acetylcholine receptors; schizophrenia.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Central Nervous System Diseases / drug therapy*
  • Humans
  • Muscarinic Agonists* / chemistry
  • Muscarinic Agonists* / pharmacology
  • Muscarinic Agonists* / therapeutic use
  • Neurosciences*
  • Pyridines* / chemistry
  • Pyridines* / pharmacology
  • Pyridines* / therapeutic use
  • Thiadiazoles* / chemistry
  • Thiadiazoles* / pharmacology
  • Thiadiazoles* / therapeutic use

Substances

  • Muscarinic Agonists
  • Pyridines
  • Thiadiazoles
  • xanomeline