Development of VU6019650: A Potent, Highly Selective, andSystemically Active Orthosteric Antagonist of the M(5)MuscarinicAcetylcholine Receptor for the Treatment of Opioid Use Disorder

The muscarinic acetylcholine receptor (mAChR)subtype 5 (M5) represents a novel potential target for thetreatment of multiple addictive disorders, including opioid usedisorder. Through chemical optimization of several functionalhigh-throughput screening hits,VU6019650(27b) was identifiedas a novel M5orthosteric antagonist with high potency (human M5IC50= 36 nM), M5subtype selectivity (>100-fold selectivity againsthuman M1???4) and favorable physicochemical properties forsystemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies,27bblocked the nonselectivemuscarinic agonist oxotremorine-M-induced increases in neuronalfiring rates of midbrain dopamine neurons in the ventraltegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover,27balso inhibited oxycodone self-administrationin male Sprague-Dawley rats within a dose range that did not impair general motor output.