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  • Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule.

Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule.

Bioorganic & medicinal chemistry letters (2013-02-19)
Michael S Poslusney, Bruce J Melancon, Patrick R Gentry, Douglas J Sheffler, Thomas M Bridges, Thomas J Utley, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley, Michael R Wood
ABSTRACT

This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Isatin, 97%
Sigma-Aldrich
Pyrrolidine, ≥99.5%, purified by redistillation
Sigma-Aldrich
Pyrrolidine, ≥99.0%
Sigma-Aldrich
Pyrrolidine, FG
Sigma-Aldrich
Pyrrolidine, 99%