Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic
- Trends Pharmacol Sci. 2022 Dec;43(12):1098-1112. doi: 10.1016/j.tips.2022.09.006.
- 1. Karuna Therapeutics, Boston, MA, USA.
- 2. University of California San Diego at Riverside, La Jolla, CA, USA. Electronic address: [email protected].
Modern interest in Muscarinic Acetylcholine Receptor (mAChR) activators for Schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's Disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for Schizophrenia.