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Review

Development of the First Selective mGlu3 NAM from an mGlu5 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
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 the First Selective mGlu3 NAM from an mGlu5 PAM Hit

Douglas J. Sheffler et al.
Free Books & Documents

Excerpt

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.

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References

    1. Solubility (PBS at pH = 7.4), Stability and Reactivity experiments were conducted at Analiza. For additional information see: http://analiza.com

    1. For information on the Ricerca Lead Profiling Screen see: https://www.eurofinspanlabs.com/Catalog

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