Development of the First CNS penetrant M5 Positive Allosteric Modulator (PAM) Based on a Novel, non-Isatin Core

A recently completed functional, high throughput screen of the Molecular Libraries Probe Production Centers Network (MLPCN) screening deck of ∼360,000 compounds conducted by SRIMSC against three of the five muscarinic receptor subtypes (M1, M4 and M5) provided a number of interesting hits. As this was the first time a directed effort had been undertaken to indentify M5 selective leads, we were very pleased by the identification of nine M5 PAMs and nine M5 antagonists, despite the complete absence of M5 agonist hits. The most promising M5 PAM hit (CID 17516658), being particularly attractive due to the absence of the isatin core shared by all previous M5 PAMs, was quickly developed into a potent, selective and CNS penetrant probe molecule ML380 (hM5 PAM EC50 = 190 nM, hM5 ACh fold-shift = 9.3, rM5 PAM EC50 = 610 nM).