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ACS Med Chem Lett. 2012 Jul 12;3(7):544-549. Epub 2012 May 22.

Metabotropic glutamate receptor 5 negative allosteric modulators as novel tools for in vivo investigation.

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  • 1Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive Baltimore, Maryland 21224.


Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have shown promising results in preclinical models for anxiety and drug abuse. Here we describe a series of aryl-substituted alkynyl analogues of the prototypic mGluR5 NAM 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1). Displacement of [(3)H]1 binding in rat brain membranes showed that several of these novel compounds displayed high affinity binding (K(i) < 10 nM) for mGluR5, with up to a 24-fold increase in affinity over 1. Replacements of the 2-position Me on the pyridyl ring of 1 along with various 3'-CN, 5'-substitutions were generally well tolerated. All of the active analogues in this series had cLogP values in the 2-5 range and displayed inverse agonist characteristics in an ELISA-based assay of G(q)α-mediated IP3 production. Compounds 7i and 7j produced in vivo effects in mouse models of anxiety-like behaviors more potently than 1 or 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP, 2), supporting their utility as in vivo tools.

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