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

While the muscarinic acetylcholine receptor mAChR subtype 5 (M) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, () showed exquisite potency (human M IC = 20 nM), good subtype selectivity (>500 fold selectivity against human M), desirable brain exposure ( = 0.68, = 0.65), and high oral bioavailability (% > 100%). () and its close analogues will support further studies of M as advanced antagonist tool compounds and play an important role in the emerging biology of M.