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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chromatography, High Pressure Liquid
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Computational Biology
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Drug Design
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Excitatory Amino Acid Agonists / chemical synthesis*
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Excitatory Amino Acid Agonists / pharmacology*
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High-Throughput Screening Assays
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Humans
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Indicators and Reagents
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Oocytes / drug effects
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Patch-Clamp Techniques
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Pyrrolidinones / chemical synthesis
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Pyrrolidinones / pharmacology
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Pyruvates / chemical synthesis
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Pyruvates / pharmacology
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Receptors, N-Methyl-D-Aspartate / agonists*
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Stereoisomerism
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Structure-Activity Relationship
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Xenopus laevis
Substances
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Excitatory Amino Acid Agonists
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Indicators and Reagents
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NR2C NMDA receptor
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Pyrrolidinones
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Pyruvates
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Receptors, N-Methyl-D-Aspartate