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

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.