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

Thomas M. Keck, Mu Fa Zou, Peng Zhang, Rebecca P. Rutledge, Amy Hauck Newman

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 G qα-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.

Original languageEnglish (US)
Pages (from-to)544-549
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number7
StatePublished - Jul 12 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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