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National Institute of Environmental Health Sciences

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Publication Detail

Title: Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.

Authors: Acker, Timothy M; Yuan, Hongjie; Hansen, Kasper B; Vance, Katie M; Ogden, Kevin K; Jensen, Henrik S; Burger, Pieter B; Mullasseril, Praseeda; Snyder, James P; Liotta, Dennis C; Traynelis, Stephen F

Published In Mol Pharmacol, (2011 Nov)

Abstract: 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 IC(50) 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.

PubMed ID: 21807990 Exiting the NIEHS site

MeSH Terms: Animals; Cells, Cultured; Cricetinae; DNA, Complementary; Excitatory Amino Acid Antagonists/chemistry; Excitatory Amino Acid Antagonists/pharmacology*; Glutamic Acid/metabolism*; Humans; Patch-Clamp Techniques; Pyrazoles/chemistry; Pyrazoles/pharmacology*; Quinolones/chemistry; Quinolones/pharmacology*; Rats; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors*; Receptors, N-Methyl-D-Aspartate/genetics; Receptors, N-Methyl-D-Aspartate/metabolism; Structure-Activity Relationship

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