Development of VU6019650 : A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M 5 Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder.

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M ₅ ) 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 M ₅ orthosteric antagonist with high potency (human M ₅ IC ₅₀ = 36 nM), M ₅ subtype selectivity (>100-fold selectivity against human M _1-4 ) 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.