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

Authors: Zimmerman, Sommer S; Khatri, Alpa; Garnier-Amblard, Ethel C; Mullasseril, Praseeda; Kurtkaya, Natalie L; Gyoneva, Stefka; Hansen, Kasper B; Traynelis, Stephen F; Liotta, Dennis C

Published In J Med Chem, (2014 Mar 27)

Abstract: NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca(2+)-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.

PubMed ID: 24512267

MeSH Terms: Animals; Chromatography, High Pressure Liquid; Computational Biology; Drug Design; Excitatory Amino Acid Agonists/chemical synthesis*; Excitatory Amino Acid Agonists/pharmacology*; High-Throughput Screening Assays; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Oocytes/drug effects; Patch-Clamp Techniques; Pyrrolidinones/chemical synthesis; Pyrrolidinones/pharmacology; Pyruvates/chemical synthesis; Pyruvates/pharmacology; Receptors, N-Methyl-D-Aspartate/agonists*; Stereoisomerism; Structure-Activity Relationship; Xenopus laevis