Chemical Lead Optimization of a pan Gq mAChR M1 M3 M5 Positive Allosteric Modulator (PAM) Lead. Part I. Development of the first highly selective M5 PAM

摘要

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1–M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS.