Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators

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

Research output: Contribution to journalArticlepeer-review

Abstract

NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D 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.

Original languageEnglish
Pages (from-to)2334-2356
Number of pages23
JournalJournal of Medicinal Chemistry
Volume57
Issue number6
DOIs
StatePublished - Mar 27 2014

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