Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Molecular pharmacology, 2011-11, Vol.80 (5), p.782-795

Ort / Verlag

United States

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.