Keck Thomas M, Zou Mu-Fa, Zhang Peng, Rutledge Rebecca P, Newman Amy Hauck
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.
ACS Med Chem Lett. 2012 Jul 12;3(7):544-549. doi: 10.1021/ml3000726. Epub 2012 May 22.
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.
代谢型谷氨酸受体5（mGluR5）的负变构调节剂（NAMs）在焦虑和药物滥用的临床前模型中已显示出有前景的结果。在此，我们描述了一系列原型mGluR5 NAM 2-甲基-6-（苯乙炔基）吡啶（MPEP，1）的芳基取代炔基类似物。在大鼠脑膜中对[（3）H]1结合的置换显示，这些新型化合物中的几种对mGluR5表现出高亲和力结合（K（i）<10 nM），与1相比亲和力增加高达24倍。1吡啶环上2位甲基的取代以及各种3'-CN、5'-取代通常耐受性良好。该系列中的所有活性类似物的cLogP值在2-5范围内，并且在基于ELISA的G（q）α介导的IP3产生测定中表现出反向激动剂特性。化合物7i和7j在焦虑样行为小鼠模型中产生的体内效应比1或3-（（2-甲基-1,3-噻唑-4-基）乙炔基）吡啶（MTEP，2）更强，支持它们作为体内工具的效用。
