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Development of : A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder

Authors

Garrison AT Aaron T , Orsi DL Douglas L , Capstick RA Rory A , Whomble D David , Li J Jinming , Carter TR Trever R , Felts AS Andrew S , Vinson PN Paige N , Rodriguez AL Alice L , Han A Allie , Hajari K Krishma , Cho HP Hyekyung P , Teal LB Laura B , Ragland MG Madeline G , Ghamari-Langroudi M Masoud , Bubser M Michael , Chang S Sichen , Schnetz-Boutaud NC Nathalie C , Boutaud O Olivier , Blobaum AL Anna L , Foster DJ Daniel J , Niswender CM Colleen M , Conn PJ P Jeffrey , Lindsley CW Craig W , Jones CK Carrie K , Han C Changho .
Journal of medicinal chemistry. 2022 04 13; 65(8).
6273-6286

Abstract

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M) 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, () was identified as a novel M orthosteric antagonist with high potency (human M IC = 36 nM), M subtype selectivity (>100-fold selectivity against human M) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, 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, also inhibited oxycodone self-administration in male Sprague-Dawley rats within a dose range that did not impair general motor output.