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鈥?CN, 5鈥?substitutions were generally well tolerated. All of the active analogues in this series had cLog
P values in the 2鈥? range and displayed inverse agonist characteristics in an ELISA-based assay of G
q伪-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.
Keywords:
glutamate; negative allosteric modulator; inverse agonist; anxiety; light鈭抎ark box
