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Development of the First Selective mGlu 3 NAM from an mGlu 5 PAM Hit

Development of the First Selective mGlu 3 NAM from an mGlu 5 PAM Hit

Douglas J. Sheffler, Cody J. Wenthur, Joshua A. Brunner, J. Scott Daniels, Ryan D. Morrison, Anna L. Blobaum, Eric S. Dawson, Julie L. Engers, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley

PMID: 23762947

Abstract:

Herein we report the discovery and structure activity relationship (SAR) of a novel metabotropic glutamate receptor 3 (mGlu3) negative allosteric modulators (NAM) probe (ML289) with 15-fold selectivity versus mGlu2 (IC50 >10 μM). The mGlu3 NAM was discovered via a 'molecular switch' from a closely related, potent (EC50 = 197 nM) mGlu5 positive allosteric modulator (PAM), CID 16000100. This mGlu3 NAM (CID 56587994, ML289) displays an IC50 value of 649 nM and is inactive on mGlu5 (>30 μM) and clean in a Ricerca ancillary pharmacology panel. ML289 possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. Thus, ML289 is a best-in-class in vitro and in vivo probe for studying non-competitive antagonism of mGlu3.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1382481799	ML289		1382481-79-9	Price

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