title: Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
abstract: 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.
authors.affiliation: Department of Chemistry, Emory University, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Acker
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Katie M
authors.initials: KM
authors.lastname: Vance
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ogden
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Jensen
authors.forename: Pieter B
authors.initials: PB
authors.lastname: Burger
authors.forename: Praseeda
authors.initials: P
authors.lastname: Mullasseril
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D018076:DNA, Complementary; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C568654:4-(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; D018076:DNA, Complementary; D018691:Excitatory Amino Acid Antagonists; D011720:Pyrazoles; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid