title: Metabotropic glutamate receptor 5 negative allosteric modulators as novel tools for in vivo investigation.
abstract: 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.
authors.affiliation: Medicinal 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.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keck
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Rutledge
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman