Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators as Novel Tools for in Vivo Investigation

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• 作者：Thomas M. Keck ; Mu-Fa Zou ; Peng Zhang ; Rebecca P. Rutledge ; Amy Hauck Newman
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：3
• 期：7
• 页码：544-549
• 全文大小：293K
• 年卷期：v.3,no.7(July 12, 2012)
• ISSN：1948-5875

文摘

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 (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