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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.

SUBMITTER: Zimmerman SS

PROVIDER: S-EPMC3983368 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Zimmerman Sommer S SS Khatri Alpa A Garnier-Amblard Ethel C EC Mullasseril Praseeda P Kurtkaya Natalie L NL Gyoneva Stefka S Hansen Kasper B KB Traynelis Stephen F SF Liotta Dennis C DC

Journal of medicinal chemistry 20140225 6

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 recombin ...[more]

PMID: 24512267

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