New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III

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• 作者：Tri H. V. Huynh ; Mette N. Erichsen ; Amélie S. Tora ; Cyril Goudet ; Emmanuelle Sagot ; Zeinab Assaf ; Christian Thomsen ; Robb Brodbeck ; Tine B. Stensb?l ; Walden E. Bj?rn-Yoshimoto ; Birgitte Nielsen ; Jean-Philippe Pin ; Thierry Gefflaut ; Lennart Bunch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：914-924
• 全文大小：665K
• ISSN：1520-4804

文摘

The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6–8). In this article, we present a L-2,4-syn-substituted Glu analogue, <b>1db>, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, <b>2ab>–<b>db>. Most interestingly, <b>2ab> retained a selective agonist activity profile at mGlu2 (ECb>50b> in the micromolar range), whereas <b>2cb>/<b>2db> were both selective agonists at group III, subtypes mGlu4,6,8. In general, <b>2db> was 20-fold more potent than <b>2cb> and potently activated mGlu4,6,8 in the low–mid nanomolar range.