Muscarinic acetylcholine receptor M2, M3, M4, and M5 (CHRM2, CHRM3, CHRM4, CHRM5)

Muscarinic acetylcholine receptors M2, M3, M4, and M5 are G protein-coupled receptors (GPCRs) that mediate the diverse physiological actions of acetylcholine in the central and peripheral nervous systems (UniProt P08172, P20309, P08173, P08912). While xanomeline is primarily targeted as an M1/M4-preferring agonist for the treatment of schizophrenia and Alzheimer's disease, it exhibits significant off-target binding and activation of the M2, M3, and M5 subtypes (PubChem CID 63357). Activation of M2 receptors, found predominantly in the heart and presynaptic terminals, leads to a decrease in heart rate (bradycardia) and inhibition of neurotransmitter release (Nature Reviews Drug Discovery, 2014). M3 receptor activation in smooth muscles and exocrine glands results in increased gastrointestinal motility, bronchoconstriction, and glandular secretions (Nature Reviews Drug Discovery, 2014). These off-target interactions are responsible for the characteristic cholinergic side effects of xanomeline, such as nausea, vomiting, and diaphoresis, which historically limited its clinical use (Nature Reviews Drug Discovery, 2022). To mitigate these effects, xanomeline is now often co-administered with peripheral muscarinic antagonists like trospium chloride, which block the off-target peripheral receptors without crossing the blood-brain barrier (Cobenfy Prescribing Information).

Other names

mAChR M2-M5Muscarinic receptorsCholinergic receptor muscarinic 2, 3, 4, and 5

Xanomeline acts as an agonist at these receptors; M2 and M4 are Gi-coupled (inhibitory), while M3 and M5 are Gq-coupled (excitatory). Off-target activation of peripheral M2 and M3 receptors by xanomeline results in cholinergic adverse events.