RT Journal Article
SR Electronic
T1 Mechanism for Non-competitive Inhibition by Novel GluN2C/D NMDA Receptor Subunit-selective Modulators
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.073239
DO 10.1124/mol.111.073239
A1 Timothy Acker
A1 Hongjie Yuan
A1 Kasper B Hansen
A1 Katie M Vance
A1 Kevin K. Ogden
A1 Henrik S. Jensen
A1 Pieter B. Burger
A1 Praseeda Mullasseril
A1 James P. Snyder
A1 Dennis C. Liotta
A1 Stephen F. Traynelis
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/08/02/mol.111.073239.abstract
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 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 could not be surmounted by increasing concentrations of either co-agonists glutamate or glycine, consistent with a non-competitive 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 pre-gating 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.