Development of VU6019650: A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M₅ Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder

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.

Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner

“…which may produce differential effects on evoked DA release in the NAc compared to allosteric modulators (Garrison et al, 2022). Apparent sex differences emerged in the ability of physostigmine, when co-administered with VU6000181, to increase evoked phasic DA release in males but not females.…”

Development of VU6036864: A Triazolopyridine-Based High-Quality Antagonist Tool Compound of the M5 Muscarinic Acetylcholine Receptor

“…6-(1-((2,3-Dihydrobenzofuran-5-yl)sulfonyl)piperidin-4-yl)-5methyl- [1,2,4]triazolo [1,5-a]pyridine (11). Compound 11 was synthesized according to exemplary synthetic procedure (12.7 mg).…”

G protein-coupled receptor modulation of striatal dopamine transmission: Implications for substance use disorders

“…Because M5 expression is relatively restricted to dopamine neurons, there has been significant interest in targeting M5 in disorders that involve dopamine dysregulation, including substance use disorders . For example, M5-selective negative allosteric modulators (NAMs) that block oxotremorine-induced firing of VTA neurons reduce opioid self-administration and opioid-associated cue reactivity in rats (Garrison et al, 2022;Gould et al, 2019). An M5 NAM also reduces cocaine selfadministration in both fixed ratio and progressive ratio tasks (Gunter et al, 2018).…”