期刊
MOLECULAR PHARMACOLOGY
卷 80, 期 5, 页码 782-795出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.111.073239
关键词
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资金
- Michael J. Fox Foundation
- National Institutes of Health National Institutes of Neurological Disorders and Stroke [R01-NS036654, R01-NS065371, F31-NS071802]
- National Institutes of Health National Institute of General Medical Sciences [T32-GM008602]
- National Institutes of Health National Institute on Drug Abuse [T32-DA01504006]
- National Institutes of Health National Institute of Environmental Health Sciences [T32-ES012870]
- Villum Kann Rasmussen Foundation
- Lundbeck Foundation
- Emory University from Pfizer Inc.
- Lundbeck AS
- Emory Chemistry Biology Discovery Center
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.
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