Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Med Chem
2010 Aug 12;5315:5476-90. doi: 10.1021/jm100027p.
Show Gene links
Show Anatomy links
Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists.
Mosley CA
,
Acker TM
,
Hansen KB
,
Mullasseril P
,
Andersen KT
,
Le P
,
Vellano KM
,
Bräuner-Osborne H
,
Liotta DC
,
Traynelis SF
.
???displayArticle.abstract???
We describe a new class of subunit-selective antagonists of N-methyl D-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), a noncompetitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of noncompetitive subunit-selective NMDA receptor antagonists.
???displayArticle.pubmedLink???
20684595
???displayArticle.pmcLink???PMC2920070 ???displayArticle.link???J Med Chem ???displayArticle.grants???[+]
Akazawa,
Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats.
1994, Pubmed
Akazawa,
Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats.
1994,
Pubmed
Bräuner-Osborne,
Ligands for glutamate receptors: design and therapeutic prospects.
2000,
Pubmed
Brothwell,
NR2B- and NR2D-containing synaptic NMDA receptors in developing rat substantia nigra pars compacta dopaminergic neurones.
2008,
Pubmed
Buller,
The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition.
1994,
Pubmed
,
Xenbase
Carter,
Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. II. Evidence for N-methyl-D-aspartate receptor antagonist properties.
1988,
Pubmed
Chen,
Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling.
2005,
Pubmed
,
Xenbase
Colonnese,
Chronic NMDA receptor blockade from birth delays the maturation of NMDA currents, but does not affect AMPA/kainate currents.
2003,
Pubmed
Dirnagl,
Pathobiology of ischaemic stroke: an integrated view.
1999,
Pubmed
Dravid,
Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block.
2007,
Pubmed
,
Xenbase
Dunah,
Subunit composition of N-methyl-D-aspartate receptors in the central nervous system that contain the NR2D subunit.
1998,
Pubmed
Dunah,
Regional and ontogenic expression of the NMDA receptor subunit NR2D protein in rat brain using a subunit-specific antibody.
1996,
Pubmed
Dunah,
Subcellular segregation of distinct heteromeric NMDA glutamate receptors in the striatum.
2003,
Pubmed
Erreger,
Glutamate receptor gating.
2004,
Pubmed
Erreger,
Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog.
2005,
Pubmed
,
Xenbase
Erreger,
Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles.
2005,
Pubmed
Feng,
Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid.
2004,
Pubmed
,
Xenbase
Frizelle,
Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: Implications for studies of synaptic transmission.
2006,
Pubmed
,
Xenbase
Furukawa,
Subunit arrangement and function in NMDA receptors.
2005,
Pubmed
Gotti,
Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia.
1988,
Pubmed
Hallett,
Rationale for and use of NMDA receptor antagonists in Parkinson's disease.
2004,
Pubmed
Hansen,
Pharmacological characterization of ligands at recombinant NMDA receptor subtypes by electrophysiological recordings and intracellular calcium measurements.
2008,
Pubmed
,
Xenbase
Hansen,
Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.
2010,
Pubmed
,
Xenbase
Hess,
Functional characterization of human N-methyl-D-aspartate subtype 1A/2D receptors.
1998,
Pubmed
,
Xenbase
Káradóttir,
NMDA receptors are expressed in oligodendrocytes and activated in ischaemia.
2005,
Pubmed
Karakas,
Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit.
2009,
Pubmed
,
Xenbase
Karavanova,
Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice.
2007,
Pubmed
Lau,
Differential expression of N-methyl-D-aspartate receptor subunit messenger ribonucleic acids and immunoreactivity in the rat neostriatum during postnatal development.
2003,
Pubmed
Lazzaro,
Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist.
2002,
Pubmed
Lindahl,
Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine.
2004,
Pubmed
Lisman,
Long-term potentiation: outstanding questions and attempted synthesis.
2003,
Pubmed
Lopez de Armentia,
Development and subunit composition of synaptic NMDA receptors in the amygdala: NR2B synapses in the adult central amygdala.
2003,
Pubmed
Mayer,
Structure and function of glutamate receptor ion channels.
2004,
Pubmed
Menniti,
Characterization of the binding site for a novel class of noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonists.
2000,
Pubmed
Miyabe,
Comparative analysis of brain protection by N-methyl-D-aspartate receptor antagonists after transient focal ischemia in cats.
1997,
Pubmed
Miyamoto,
Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus.
2006,
Pubmed
Monyer,
Heteromeric NMDA receptors: molecular and functional distinction of subtypes.
1992,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Morley,
Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists.
2005,
Pubmed
,
Xenbase
Nacher,
The role of N-methyl-D-asparate receptors in neurogenesis.
2006,
Pubmed
Neyton,
Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach.
2006,
Pubmed
Paquet,
AMPA and NMDA glutamate receptor subunits in midbrain dopaminergic neurons in the squirrel monkey: an immunohistochemical and in situ hybridization study.
1997,
Pubmed
Preskorn,
How multiple medication use evolves and the importance of therapeutic trials: the slippery slide.
2008,
Pubmed
Rudhard,
Absence of Whisker-related pattern formation in mice with NMDA receptors lacking coincidence detection properties and calcium signaling.
2003,
Pubmed
Salter,
NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury.
2005,
Pubmed
Sobolevsky,
Probing of NMDA channels with fast blockers.
1999,
Pubmed
Stern,
Single-channel conductances of NMDA receptors expressed from cloned cDNAs: comparison with native receptors.
1992,
Pubmed
,
Xenbase
Thompson,
Immunohistochemical localization of N-methyl-D-aspartate receptor subunits in the adult murine hippocampal formation: evidence for a unique role of the NR2D subunit.
2002,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Walsh,
Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
2008,
Pubmed
Wang,
NMDA/NR2B selective antagonists in the treatment of ischemic brain injury.
2005,
Pubmed
Waters,
Role of NMDA receptors in development of respiratory control.
2005,
Pubmed
Welch,
Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.
2001,
Pubmed
Whetsell,
Current concepts of excitotoxicity.
1996,
Pubmed
Williams,
Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
1993,
Pubmed
,
Xenbase
Wyllie,
Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors.
1998,
Pubmed
,
Xenbase
Yuan,
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
2009,
Pubmed
,
Xenbase
