Xanomeline

Pharmacodynamics Muscarinic acetylcholine receptor agonist Xanomeline is an agonist that primarily targets the muscarinic acetylcholine receptor family of five muscarinic receptor subtypes, which are designated M1-M5. In addition to its muscarinic acetylcholine M1 and M4 receptor agonism, xanomeline has been found to act as an antagonist or partial agonist of the M5 receptor. Other actions Aside from its actions at the muscarinic acetylcholine receptors, xanomeline has relatively high affinity for certain other targets, such as various serotonin receptors. Xanomeline may inhibit CYP3A4 and P-glycoprotein locally in the intestines, but does not inhibit them systemically. Xanomeline has shown antipsychotic-like effects in various preclinical behavioral models, such as attenuation of amphetamine-induced locomotor hyperactivity, Pharmacokinetics CYP2D6 significantly contributes to the metabolism of xanomeline. As a result, CYP2D6 polymorphisms are expected to affect the patient's exposure to xanomeline. == Chemistry ==

Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient in betel nut, arecoline, and the natural muscarinic receptor neurotransmitter, acetylcholine. Xanomeline is an achiral and lipophilic small molecule with a molecular weight of 281.4 (also known as hexyloxy-TZTP, LY246708, Lumeron, Memcor - Eli Lilly; NNC 11-0232 - Novo Nordisk; Kar-XT, Karuna Therapeutics). Xanomeline's physical chemical properties, including low molecular weight, lipophilicity, and absence of hydrogen bond donors, favor its entry into the brain with a high brain to plasma ratio (> 10:1). == Clinical development ==

Xanomeline was first discovered in a therapeutic development collaboration between Eli Lilly & Co. and Novo Nordisk pharmaceutical companies in the early 1990s. A small placebo-controlled study in treatment-resistant schizophrenia followed, demonstrating its antipsychotic-like action. Xanomeline's development was discontinued primarily due to cholinergic side effects observed in clinical studies . Further development was enabled through a novel co-formulation strategy, xanomeline/trospium (developmental name KarXT), with the peripherally restricted muscarinic antagonist, trospium, to quell the peripheral cholinergic side effects. In September 2024, the combination drug was approved by the FDA. == References ==