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

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M-5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M-1, M-3, M-5 PAM. An iterative library synthesis approach delivered the first selective M-5 PAM (no activity at M-1-M-4 @ 30 mu M), and an important tool compound to study the role of M-5 in the CNS. (C) 2009 Elsevier Ltd. All rights reserved.