Positive and Negative Modulation of Group I Metabotropic Glutamate Receptors

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• 作者：Maksims Vanejevs ; Claudia Jatzke ; Steffen Renner ; Sibylle Mü ; ller ; Mirko Hechenberger ; Tanja Bauer ; Anna Klochkova ; Ilya Pyatkin ; Denis Kazyulkin ; Elena Aksenova ; Sergey Shulepin ; Olga Timonina ; A
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：634 - 647
• 全文大小：823K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor’s transmembrane domain was visualized.