Category: receptor_pharmacology
Muscarinic ACh receptors (mAChRs) are GPCRs — distinct from nicotinic ([[nicotinic_ach_receptor_pharmacology]]). Five subtypes with conserved Gq vs Gi coupling pattern: M1, M3, M5 → Gq → PLC → IP3 + DAG → Ca²⁺ mobilization (excitatory). M2, M4 → Gi → ↓cAMP + ↑GIRK K⁺ channels (inhibitory). Tissue distribution: M1 = CNS (cortex, hippocampus — cognitive function); M2 = cardiac (SA + AV node — bradycardia; vagal heart-rate slowing); M3 = smooth muscle (bronchial, GI, bladder, vascular endothelium NO release) + glands (salivary, lacrimal); M4 = CNS (striatum); M5 = CNS (VTA — implicated in addiction). Therapeutic challenges: most clinically-used "anticholinergics" lack subtype selectivity → broad side effects (dry mouth, blurred vision, urinary retention, constipation, cognitive impairment in elderly = "anticholinergic burden" — dementia association in long-term use). Subtype-targeted programs are difficult — orthosteric binding pocket is highly conserved. PAMs for M1 (xanomeline/trospium combo — KarXT, FDA-approved 2024 for schizophrenia) achieve selectivity via less-conserved allosteric sites. M3-selective inhaled bronchodilators (tiotropium, umeclidinium, aclidinium) minimize systemic load. Urinary M3 antagonists (oxybutynin, tolterodine, solifenacin, darifenacin, trospium, fesoterodine) for overactive bladder. M2-selective drugs not clinically used (cardiac vagal effect dangerous). Cross-links: [[acetylcholine_axis]] (ACh synthesis + AChE), [[autonomic_balance]] (parasympathetic output is M-receptor-mediated), [[bladder_detrusor_pharmacology]] (M3 urinary).