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Acker, T.M. et al.

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 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.[1]

References

Mechanism for Noncompetitive Inhibition by Novel GluN2C/D N-Methyl-D-aspartate Receptor Subunit-Selective Modulators. Acker, T.M., Yuan, H., Hansen, K.B., Vance, K.M., Ogden, K.K., Jensen, H.S., Burger, P.B., Mullasseril, P., Snyder, J.P., Liotta, D.C., Traynelis, S.F. Mol. Pharmacol. (2011) [Pubmed]

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