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Review

Development of a Second Generation mGlu3 NAM Probe

Cody Wenthur  1 , J. Scott Daniels  1 , Ryan Morrison  1 , Julie L. Engers  1 , Colleen M. Niswender  1 , P. Jeffrey Conn  1 , Craig W. Lindsley  1
In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010.
[updated ].
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Review

Development of a Second Generation mGlu3 NAM Probe

Cody Wenthur et al.
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Excerpt

Herein we report the discovery and structure activity relationship (SAR) of a novel, second generation metabotropic glutamate receptor 3 (mGlu3) negative allosteric modulator (NAM) probe (ML337) with >50-fold selectivity versus mGlu2 (IC50 >30 μM). The mGlu3 NAM was discovered via an iterative parallel synthesis optimization of the first generation mGlu3 NAM ML289, that was only ~15-fold selective. This mGlu3 NAM (60204017, ML337) displays an IC50 value of 592 nM and is inactive (>30 μM) on mGlu2 (as well as mGlu1,4,5,6,7,8) and clean in a Ricerca ancillary pharmacology panel. ML337 possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. Thus, ML337 is a best-in-class in vitro and in vivo probe for studying non-competitive antagonism of mGlu3.

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References

    1. Niswender CM, Johnson KA, Luo Q, Ayala JE, Kim C, Conn PJ, Weaver CD. Mol. Pharm. 2008;73:1213–1224. - PubMed

    1. For full information on the targets in the Lead Profiling Screen at Ricerca, please see: www.ricerca.com

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