Development of <b>VU6019650</b>: A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M<sub>5</sub> Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder
Aaron T. Garrison, Douglas L. Orsi, Rory A. Capstick, David Whomble, Jinming Li, Trever R. Carter, Andrew S. Felts, Paige N. Vinson, Alice L. Rodriguez, Allie Han, Krishma Hajari, Hyekyung P. Cho, Laura B. Teal, Madeline G. Ragland, Masoud Ghamari‐Langroudi, Michael Bubser, Sichen Chang, Nathalie Schnetz‐Boutaud, Olivier Boutaud, Anna L. Blobaum, Daniel J. Foster, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Carrie K. Jones, Changho Han
Abstract
The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) represents a novel potential target for the treatment of multiple addictive disorders, including opioid use disorder. Through chemical optimization of several functional high-throughput screening hits, VU6019650 (27b) was identified as a novel M5 orthosteric antagonist with high potency (human M5 IC50 = 36 nM), M5 subtype selectivity (>100-fold selectivity against human M1-4) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, 27b blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover, 27b also inhibited oxycodone self-administration in male Sprague-Dawley rats within a dose range that did not impair general motor output.