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

Poslusney MS, Melancon BJ, Gentry PR, Sheffler DJ, Bridges TM, Utley TJ, Daniels JS, Niswender CM, Conn PJ, Lindsley CW, Wood MR
Bioorg Med Chem Lett. 2013 23 (6): 1860-4

PMID: 23416001 · PMCID: PMC3594472 · DOI:10.1016/j.bmcl.2013.01.017

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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (10)

Allosteric Regulation Animals Humans Isatin Protein Binding Pyrrolidines Rats Receptor, Muscarinic M1 Spiro Compounds Structure-Activity Relationship

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