Design, Synthesis, and Structure鈥揂ctivity Relationship of a Novel Series of GluN2C-Selective Potentiators

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• 作者：Sommer S. Zimmerman ; Alpa Khatri ; Ethel C. Garnier-Amblard ; Praseeda Mullasseril ; Natalie L. Kurtkaya ; Stefka Gyoneva ; Kasper B. Hansen ; Stephen F. Traynelis ; Dennis C. Liotta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2334-2356
• 全文大小：796K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A鈥揇 subunits that mediate a slow Ca²⁺-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.