title: Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators.
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.
authors: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors: Sommer S
authors: SS
authors: Zimmerman
authors: Alpa
authors: A
authors: Khatri
authors: Ethel C
authors: EC
authors: Garnier-Amblard
authors: Praseeda
authors: P
authors: Mullasseril
authors: Natalie L
authors: NL
authors: Kurtkaya
authors: Stefka
authors: S
authors: Gyoneva
authors: Kasper B
authors: KB
authors: Hansen
authors: Stephen F
authors: SF
authors: Traynelis
authors: Dennis C
authors: DC
authors: Liotta
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology; D011773:Pyruvates / Q000138:chemical synthesis / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D018690:Excitatory Amino Acid Agonists; D007202:Indicators and Reagents; C432823:NR2C NMDA receptor; D011760:Pyrrolidinones; D011773:Pyruvates; D016194:Receptors, N-Methyl-D-Aspartate