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Neuropharmacology
2013 Dec 01;75:324-36. doi: 10.1016/j.neuropharm.2013.08.003.
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Structure-based discovery of antagonists for GluN3-containing N-methyl-D-aspartate receptors.
Kvist T
,
Greenwood JR
,
Hansen KB
,
Traynelis SF
,
Bräuner-Osborne H
.
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NMDA receptors are ligand-gated ion channels that assemble into tetrameric receptor complexes composed of glycine-binding GluN1 and GluN3 subunits (GluN3A-B) and glutamate-binding GluN2 subunits (GluN2A-D). NMDA receptors can assemble as GluN1/N2 receptors and as GluN3-containing NMDA receptors, which are either glutamate/glycine-activated triheteromeric GluN1/N2/N3 receptors or glycine-activated diheteromeric GluN1/N3 receptors. The glycine-binding GluN1 and GluN3 subunits display strikingly different pharmacological selectivity profiles. However, the pharmacological characterization of GluN3-containing receptors has been hampered by the lack of methods and pharmacological tools to study GluN3 subunit pharmacology in isolation. Here, we have developed a method to study the pharmacology of GluN3 subunits in recombinant diheteromeric GluN1/N3 receptors by mutating the orthosteric ligand-binding pocket in GluN1. This method is suitable for performing compound screening and characterization of structure-activity relationship studies on GluN3 ligands. We have performed a virtual screen of the orthosteric binding site of GluN3A in the search for antagonists with selectivity for GluN3 subunits. In the subsequent pharmacological evaluation of 99 selected compounds, we identified 6-hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5(4H)-one (TK80) a novel competitive antagonist with preference for the GluN3B subunit. Serendipitously, we also identified [2-hydroxy-5-((4-(pyridin-3-yl)thiazol-2-yl)amino]benzoic acid (TK13) and 4-(2,4-dichlorobenzoyl)-1H-pyrrole-2-carboxylic acid (TK30), two novel non-competitive GluN3 antagonists. These findings demonstrate that structural differences between the orthosteric binding site of GluN3 and GluN1 can be exploited to generate selective ligands.
Andersson,
Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B.
2001, Pubmed
Andersson,
Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B.
2001,
Pubmed
Awobuluyi,
Subunit-specific roles of glycine-binding domains in activation of NR1/NR3 N-methyl-D-aspartate receptors.
2007,
Pubmed
Bjerrum,
Rigid body essential X-ray crystallography: distinguishing the bend and twist of glutamate receptor ligand binding domains.
2008,
Pubmed
Cavara,
Shuffling the deck anew: how NR3 tweaks NMDA receptor function.
2008,
Pubmed
Cavara,
Residues at the tip of the pore loop of NR3B-containing NMDA receptors determine Ca2+ permeability and Mg2+ block.
2010,
Pubmed
,
Xenbase
Chatterton,
Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.
2002,
Pubmed
,
Xenbase
Cheng,
Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.
1973,
Pubmed
Ciabarra,
Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family.
1995,
Pubmed
,
Xenbase
Das,
Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A.
1998,
Pubmed
,
Xenbase
Erreger,
Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors.
2007,
Pubmed
,
Xenbase
Furukawa,
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core.
2003,
Pubmed
Hansen,
Subunit-selective allosteric inhibition of glycine binding to NMDA receptors.
2012,
Pubmed
Henson,
Genetic deletion of NR3A accelerates glutamatergic synapse maturation.
2012,
Pubmed
Henson,
Influence of the NR3A subunit on NMDA receptor functions.
2010,
Pubmed
Herman,
The advantage of global fitting of data involving complex linked reactions.
2012,
Pubmed
Kasper,
The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209.
2006,
Pubmed
Kuryatov,
Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins.
1994,
Pubmed
,
Xenbase
Káradóttir,
NMDA receptors are expressed in oligodendrocytes and activated in ischaemia.
2005,
Pubmed
Larsen,
NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity.
2011,
Pubmed
Laube,
Evidence for a tetrameric structure of recombinant NMDA receptors.
1998,
Pubmed
,
Xenbase
Lipinski,
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.
2001,
Pubmed
Low,
New insights into the not-so-new NR3 subunits of N-methyl-D-aspartate receptor: localization, structure, and function.
2010,
Pubmed
Madry,
Principal role of NR3 subunits in NR1/NR3 excitatory glycine receptor function.
2007,
Pubmed
,
Xenbase
Martínez-Turrillas,
The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation.
2012,
Pubmed
Matsuda,
Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability.
2002,
Pubmed
Menuz,
TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists.
2007,
Pubmed
Micu,
NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.
2006,
Pubmed
Nakanishi,
Neuroprotection by the NR3A subunit of the NMDA receptor.
2009,
Pubmed
Nishi,
Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner.
2001,
Pubmed
Pachernegg,
GluN3 subunit-containing NMDA receptors: not just one-trick ponies.
2012,
Pubmed
Perez-Otano,
Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors.
2001,
Pubmed
Pérez-Otaño,
Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1.
2006,
Pubmed
Roberts,
Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation.
2009,
Pubmed
Salter,
NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury.
2005,
Pubmed
Sasaki,
Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons.
2002,
Pubmed
,
Xenbase
Smothers,
Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits.
2007,
Pubmed
Smothers,
Expression of glycine-activated diheteromeric NR1/NR3 receptors in human embryonic kidney 293 cells Is NR1 splice variant-dependent.
2009,
Pubmed
Stys,
White matter NMDA receptors: an unexpected new therapeutic target?
2007,
Pubmed
Sucher,
Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain.
1995,
Pubmed
,
Xenbase
Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Ulbrich,
Subunit counting in membrane-bound proteins.
2007,
Pubmed
,
Xenbase
Ulbrich,
Rules of engagement for NMDA receptor subunits.
2008,
Pubmed
,
Xenbase
Walters,
Prediction of 'drug-likeness'.
2002,
Pubmed
Yao,
Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A.
2006,
Pubmed
Yao,
Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors.
2008,
Pubmed
