PT  - JOURNAL ARTICLE
AU  - Timothy M. Acker
AU  - Hongjie Yuan
AU  - Kasper B. Hansen
AU  - Katie M. Vance
AU  - Kevin K. Ogden
AU  - Henrik S. Jensen
AU  - Pieter B. Burger
AU  - Praseeda Mullasseril
AU  - James P. Snyder
AU  - Dennis C. Liotta
AU  - Stephen F. Traynelis
TI  - Mechanism for Noncompetitive Inhibition by Novel GluN2C/D <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Subunit-Selective Modulators
AID  - 10.1124/mol.111.073239
DP  - 2011 Nov 01
TA  - Molecular Pharmacology
PG  - 782--795
VI  - 80
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/80/5/782.short
4100  - http://molpharm.aspetjournals.org/content/80/5/782.full
SO  - Mol Pharmacol2011 Nov 01; 80
AB  - 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.