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 Pharmacol Exp Ther
2009 Nov 01;3312:618-26. doi: 10.1124/jpet.109.156752.
Show Gene links
Show Anatomy links
N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives: preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse.
Costa BM
,
Feng B
,
Tsintsadze TS
,
Morley RM
,
Irvine MW
,
Tsintsadze V
,
Lozovaya NA
,
Jane DE
,
Monaghan DT
.
???displayArticle.abstract???
N-Methyl-d-aspartate (NMDA) receptor antagonists that are highly selective for specific NMDA receptor 2 (NR2) subunits have several potential therapeutic applications; however, to date, only NR2B-selective antagonists have been described. Whereas most glutamate binding site antagonists display a common pattern of NR2 selectivity, NR2A > NR2B > NR2C > NR2D (high to low affinity), (2S*,3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) has a low selectivity for NR2C- and NR2D-containing NMDA receptors. A series of PPDA derivatives were synthesized and then tested at recombinant NMDA receptors expressed in Xenopus laevis oocytes. In addition, the optical isomers of PPDA were resolved; the (-) isomer displayed a 50- to 80-fold greater potency than the (+) isomer. Replacement of the phenanthrene moiety of PPDA with naphthalene or anthracene did not improve selectivity. However, phenylazobenzoyl (UBP125) or phenylethynylbenzoyl (UBP128) substitution significantly improved selectivity for NR2B-, NR2C-, and NR2D-containing receptors over NR2A-containing NMDA receptors. Phenanthrene attachment at the 3 position [(2R*,3S*)-1-(phenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP141); (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP145); (2R*,3S*)-1-(9-chlorophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP160); and (2R*,3S*)-1-(9-iodophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP161)] displayed improved NR2D selectivity. UBP141 and its 9-brominated homolog (UBP145) both display a 7- to 10- fold selectivity for NR2D-containing receptors over NR2B- or NR2A-containing receptors. Schild analysis indicates that these two compounds are competitive glutamate binding site antagonists. Consistent with a physiological role for NR2D-containing receptors in the hippocampus, UBP141 (5 muM) displayed greater selectivity than PPDA for inhibiting the slow-decaying component of the NMDA receptor-mediated CA3-CA1 synaptic response in rat hippocampal slices. UBP125, UBP128, UBP141, and UBP145 may be useful tools for determining the function of NMDA receptor subtypes.
Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998, Pubmed
Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed
Auberson,
5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition.
2002,
Pubmed
Buller,
The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition.
1994,
Pubmed
,
Xenbase
Buller,
Pharmacological heterogeneity of NMDA receptors: characterization of NR1a/NR2D heteromers expressed in Xenopus oocytes.
1997,
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
Childers,
N-methyl-D-aspartate antagonists and neuropathic pain: the search for relief.
2007,
Pubmed
Choi,
Antagonizing excitotoxicity: a therapeutic strategy for stroke?
1998,
Pubmed
Clausen,
N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands.
2008,
Pubmed
,
Xenbase
Colquhoun,
Why the Schild method is better than Schild realised.
2007,
Pubmed
Diamond,
Neuronal glutamate transporters limit activation of NMDA receptors by neurotransmitter spillover on CA1 pyramidal cells.
2001,
Pubmed
Durand,
Splice variants of the N-methyl-D-aspartate receptor NR1 identify domains involved in regulation by polyamines and protein kinase C.
1993,
Pubmed
,
Xenbase
Erreger,
Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors.
2007,
Pubmed
,
Xenbase
Feng,
The effect of competitive antagonist chain length on NMDA receptor subunit selectivity.
2005,
Pubmed
,
Xenbase
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
Hansen,
Pharmacological characterization of ligands at recombinant NMDA receptor subtypes by electrophysiological recordings and intracellular calcium measurements.
2008,
Pubmed
,
Xenbase
Hardingham,
The Yin and Yang of NMDA receptor signalling.
2003,
Pubmed
Hollmann,
Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
1993,
Pubmed
,
Xenbase
Hrabetova,
Distinct NMDA receptor subpopulations contribute to long-term potentiation and long-term depression induction.
2000,
Pubmed
,
Xenbase
Ikeda,
Cloning and expression of the epsilon 4 subunit of the NMDA receptor channel.
1992,
Pubmed
,
Xenbase
Ishii,
Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits.
1993,
Pubmed
,
Xenbase
Káradóttir,
NMDA receptors are expressed in oligodendrocytes and activated in ischaemia.
2005,
Pubmed
Kinarsky,
Identification of subunit- and antagonist-specific amino acid residues in the N-Methyl-D-aspartate receptor glutamate-binding pocket.
2005,
Pubmed
,
Xenbase
Laube,
Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit.
1997,
Pubmed
Laurie,
Ligand affinities at recombinant N-methyl-D-aspartate receptors depend on subunit composition.
1994,
Pubmed
Lozovaya,
Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape 'superslow' afterburst EPSC in rat hippocampus.
2004,
Pubmed
,
Xenbase
Meldrum,
Implications for neuroprotective treatments.
2002,
Pubmed
Minami,
Characterization of the glutamatergic system for induction and maintenance of allodynia.
2001,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Mori,
Structure and function of the NMDA receptor channel.
1995,
Pubmed
Morley,
Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists.
2005,
Pubmed
,
Xenbase
Nakanishi,
Molecular diversity of glutamate receptors and implications for brain function.
1992,
Pubmed
Neyton,
Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach.
2006,
Pubmed
Sugihara,
Structures and properties of seven isoforms of the NMDA receptor generated by alternative splicing.
1992,
Pubmed
,
Xenbase
Tong,
Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons.
2008,
Pubmed
,
Xenbase
Urwyler,
Biphenyl-derivatives of 2-amino-7-phosphono-heptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonists--II. Pharmacological characterization in vivo.
1996,
Pubmed
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
