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

Excerpt

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).