Modifying Xanomeline's Toxic Properties on Human Muscarinic Acetylcholine M1-M4 Receptors

Muscarinic acetylcholine receptor agonists such as Xanomeline (C₁₄H₂₃N₃OS) have demonstrated therapeutic efficacy in schizophrenia by targeting M1 and M4 receptors, yet significant off-target interactions with M2 and M3 receptors contribute to adverse cardiovascular and urinary effects. Cobenfy is a particular drug that pairs Xanomeline with Trospium chloride to mitigate peripheral effects, yet limitations remain. This study applied computational docking and structure-based design to modify Xanomeline's molecular architecture to enhance selectivity for M1 and M4 while reducing affinity for M2 and M3. Iterative modifications included heteroatom substitutions, polar cap additions, backbone constraints, and linker geometry adjustments. Binding affinities across receptor subtypes were evaluated using Maestro Schrodinger and ADMET analyses assessed predicted toxicity, absorption, and pharmacokinetics. Modified molecules demonstrated retained or enhanced M1/M4 binding and significantly reduced M2/M3 interactions with improved toxicity profiles. These findings suggest that rational multi-target drug design can optimize receptor selectivity and safety profiles in schizophrenia therapeutics and provide a framework for future computational and experimental follow-up.