Lindsley Craig W, Wisnoski David D, Leister William H, O'brien Julie A, Lemaire Wei, Williams David L, Burno Maryann, Sur Cyrille, Kinney Gene G, Pettibone Doug J, Tiller Philip R, Smith Sheri, Duggan Mark E, Hartman George D, Conn P Jeffrey, Huff Joel R
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Department of Neuroscience, Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Med Chem. 2004 Nov 18;47(24):5825-8. doi: 10.1021/jm049400d.
This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.
本报告描述了代谢型谷氨酸受体5（mGluR5）首个中枢活性变构调节剂的发现。适当取代的N-（1,3-二苯基-1H-吡唑-5-基）苯甲酰胺（如8）已被鉴定为一类新型的mGluR5强效正变构调节剂，可增强对谷氨酸的反应。一种迭代类似物库合成方法提供了对mGluR5具有优异效力和选择性（相对于mGluR1-4、7、8）的增强剂。化合物8q在已知抗精神病药物有活性的动物行为模型中证明了体内概念验证，支持基于精神分裂症NMDA功能减退模型开发新型抗精神病药物。
