Discovery and Characterization of a Novel Subtype‐Selective M1 Allosteric Agonist for the Treatment of Alzheimer's Disease

The muscarinic acetylcholine receptors are a family of five cholinergic GPCRS, designated M 1 ‐M 5 , located throughout the central nervous system (CNS) and periphery. Due to impaired hippocampal‐dependent learning, the M 1 muscarinic receptor has long been implicated in the pathophysiology of Alzheimer's Disease (AD). While the M 1 receptor has remained a Phase III clinically‐validated target for obtaining cognitive efficacy in AD, all efforts heretofore have not met FDA approval due to a lack of muscarinic selectivity, giving rise to severe cholinergic side effects such as poor GI tolerance. The present work reports the discovery of the first truly subtype‐selective M 1 allosteric agonist, VU0184670 which possesses EC 50 and Ach max values of 150nM and 85%, respectively, with exclusive selectivity versus M 2 ‐M 5 . In addition, VU0184670 was found to robustly potentiate NMDAR current in rat hippocampal slices. Favorable pharmacokinetics were observed following intraperitoneal dosing of an analog VU0357017 in rats at 10 mg/kg, while PanLabs analysis showed no significant off‐target binding at 10μM, providing a clear window with which to perform in vivo studies. The discovery of a potent, truly selective M1 allosteric agonist represents a significant breakthrough for AD treatment and will provide a critical basic tool to allow dissection of M 1 ‐mediated efficacy in other disease states such as Schizophrenia.