Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators as Novel Tools for in Vivo Investigation
journal contributionposted on 12.07.2012, 00:00 by Thomas M. Keck, Mu-Fa Zou, Peng Zhang, Rebecca P. Rutledge, Amy Hauck Newman
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 [3H]1 binding in rat brain membranes showed that several of these novel compounds displayed high affinity binding (Ki < 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 cLog P values in the 2–5 range and displayed inverse agonist characteristics in an ELISA-based assay of Gqα-mediated IP3 production. Compounds 7i and 7j produced in vivo effects in mouse models of anxiety-like behaviors more potently than 1 or 3-3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP, 2), supporting their utility as in vivo tools.
Read the peer-reviewed publication
affinity bindingNAManaloguemetabotropic glutamate receptor subtype 5methyl10 nMNovel ToolsseriesAllosteric Modulatorsvivo effectsMTEPnovel compoundsMetabotropic Glutamate Receptor 5rat brain membranesMPEPVivo InvestigationNegative allosteric modulatorsagonist characteristicsvivo toolsCNpyridyl ring7 jCompounds 7 i1. Replacementsdrug abusemGluRIPcLog P valuesmouse models