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

ABSTRACT: While the muscarinic acetylcholine receptor mAChR subtype 5 (M₅) 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 M₅ antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 (45) showed exquisite potency (human M₅ IC₅₀ = 20 nM), good subtype selectivity (>500 fold selectivity against human M_1-4), desirable brain exposure (K_p = 0.68, K_p,uu = 0.65), and high oral bioavailabilit

SUBMITTER: Li J 

PROVIDER: S-EPMC11345818 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature