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 IC50 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.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the Michael J. Fox Foundation; the National Institutes of Health National Institutes of Neurological Disorders and Stroke [Grants R01-NS036654, R01-NS065371, F31-NS071802]; the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM008602]; the National Institutes of Health National Institute on Drug Abuse [Grant T32-DA01504006]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES012870]; the Villum Kann Rasmussen Foundation; the Lundbeck Foundation; Research Grants to Emory University from Pfizer Inc. and Lundbeck AS; and the Emory Chemistry Biology Discovery Center.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.073239.
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ABBREVIATIONS:
- NMDA
- N-methyl-d-aspartate
- HEK
- human embryonic kidney
- MK801
- dizocilpine maleate
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- PDB
- Protein Data Bank
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- DMSO
- dimethyl sulfoxide
- DQP
- dihydroquinolone-pyrazoline-containing
- DQP-997
- 3; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1105
- 19; 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-1209
- 9; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(2-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1210
- 22; 4-(3-(6-bromo-4-phenylquinolin-3-yl)-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1308
- 18; 4-(3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1309
- 21; 6-bromo-3-(5-(4-bromophenyl)-1-propionyl-4,5-dihydro-1H-pyrazol-3-yl)-4-phenylquinolin-2(1H)-one
- DQP-1177
- 25; 4-(3-(4-bromophenyl)-5-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1178
- 8; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1183
- 1; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1184
- 2; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1185
- 5; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-2003
- 7; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(2,5-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1250
- 24; 3-(1-acetyl-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-6-methyl-4-phenylquinolin-2(1H)-one) and
- DQP-2005
- 20; 4-(5-(2-methoxyphenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-2033
- 4; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(4-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
- DQP-1128
- 6; 4-(3-(6-bromo-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid.
- Received April 25, 2011.
- Accepted August 1, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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