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

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...

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Bibliographic Details
Published in:Molecular pharmacology 2011-11, Vol.80 (5), p.782-795
Main 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
Format: Article
Language:English
Subjects:
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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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.111.073239