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Identification of a Glycine Sulfonamide Based non-MPEP Site Positive Allosteric Potentiator (PAM) of mGlu

Identification of a Glycine Sulfonamide Based non-MPEP Site Positive Allosteric Potentiator (PAM) of mGlu

Alice L. Rodriguez, James C. Tarr, Ya Zhou, Richard Williams, Karen J. Gregory, Thomas M. Bridges, J. Scott Daniels, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Shaun R. Stauffer

PMID: 24027804

Abstract:

Allosteric modulators for G-protein-coupled receptors (GPCRs) provide numerous advantages over orthosteric ligands, including greater sub-type selectivity, reduced receptor desensitization, and potential for enhanced therapeutic index. Positive allosteric modulators (PAMs) of the group I metabotropic glutamate receptor mGlu5 are being pursued as a novel approach to treat all three symptom domains of schizophrenia. mGlu5 PAMs have been reported representing diverse chemotypes, however, the majority of these bind at an allosteric binding site known as the MPEP-site. Only two classes of non-MPEP site PAMs have been reported to date, CPPHA and VU0357121, and there in vivo profile could not be established due to a lack of rat receptor potency and/or adequate dystrophia myotonica protein kinase (DMPK) properties for systemic dosing. Here we describe the structure activity relationship (SAR) and in vitro profile of a novel chemical class of mGlu5 selective PAMs which appear to exert their activity outside the MPEP site and provide more favorable physicochemical properties relative to prior art. VU0400100 (ML332, SID 144241527/CID 60210882) is a non-MPEP mGlu5 PAM with a unique glycine sulfonamide substructure and is being declared as a Molecular Libraries Probe Centers Network (MLPCN) probe molecule.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP433967283	VU0357121		433967-28-3	Price

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