Development of a Novel, Orthosteric M5 Antagonist Possessing a High Degree of Muscarinic Subtype Selectivity

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 Scripps Research Institute Molecular Screening Center (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 Positive Allosteric Modulators (PAMs) and nine M₅ antagonists, despite the complete absence of M₅ agonist hits. One of the most promising M₅ inhibitor hits (CID 49720517), was rapidly optimized into a highly mAChR subtype selective M5 orthosteric antagonist, ML381 (hM₅ IC₅₀ = 450 nM, hM_1-4 IC₅₀s >30 μM), with good Dystrophia Myotonica-Protein Kinase (DMPK) properties and Central Nervous System (CNS) penetration (B:P ratio of 0.58) to support both in vitro and in vivo studies.