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Author Notes:

Address correspondence to: Stephen F. Traynelis, Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road, Atlanta GA 30322. E-mail: strayne@emory.edu


Research Funding:

This work was supported by the Michael J. Fox Foundation; the National Institutes of Health National Institutes of Neurological Disorders and Stroke [Grants R01-NS036654, R01-NS065371, F31-NS071802]; the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM008602]; the National Institutes of Health National Institute on Drug Abuse [Grant T32-DA01504006]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES012870]; the Villum Kann Rasmussen Foundation; the Lundbeck Foundation; Research Grants to Emory University from Pfizer Inc. and Lundbeck AS; and the Emory Chemistry Biology Discovery Center.

Mechanism for Noncompetitive Inhibition by Novel GluN2C/D N-Methyl-d-aspartate Receptor Subunit-Selective Modulators

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Journal Title:

Molecular Pharmacology


Volume 80, Number 5


, Pages 782-795

Type of Work:

Article | Post-print: After Peer Review


The compound 4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (DQP-1105) is a representative member of a new class of N-methyl-d-aspartate (NMDA) receptor antagonists. DQP-1105 inhibited GluN2C- and GluN2D-containing receptors with IC50 values that were at least 50-fold lower than those for recombinant GluN2A-, GluN2B-, GluA1-, or GluK2-containing receptors. Inhibition was voltage-independent and could not be surmounted by increasing concentrations of either coagonist, glutamate or glycine, consistent with a noncompetitive mechanism of action. DQP-1105 inhibited single-channel currents in excised outside-out patches without significantly changing mean open time or single-channel conductance, suggesting that DQP inhibits a pregating step without changing the stability of the open pore conformation and thus channel closing rate. Evaluation of DQP-1105 inhibition of chimeric NMDA receptors identified two key residues in the lower lobe of the GluN2 agonist binding domain that control the selectivity of DQP-1105. These data suggest a mechanism for this new class of inhibitors and demonstrate that ligands can access, in a subunit-selective manner, a new site located in the lower, membrane-proximal portion of the agonist-binding domain.

Copyright information:

Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics

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