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.
Proc Natl Acad Sci U S A
2001 Mar 13;986:3519-24. doi: 10.1073/pnas.061449498.
Show Gene links
Show Anatomy links
An N-methyl-D-aspartate receptor channel blocker with neuroprotective activity.
Tai KK
,
Blondelle SE
,
Ostresh JM
,
Houghten RA
,
Montal M
.
???displayArticle.abstract???
Excitotoxicity, resulting from sustained activation of glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype, is considered to play a causative role in the etiology of ischemic stroke and several neurodegenerative diseases. The NMDA receptor is therefore a target for the development of neuroprotective agents. Here, we identify an N-benzylated triamine (denoted as NBTA) as a highly selective and potent NMDA-receptor channel blocker selected by screening a reduced dipeptidomimetic synthetic combinatorial library. NBTA blocks recombinant NMDA receptors expressed in Xenopus laevis oocytes with a mean IC(50) of 80 nM; in contrast, it does not block GluR1, a glutamate receptor of the non-NMDA subtype. The blocking activity of NBTA on NMDA receptors exhibits the characteristics of an open-channel blocker: (i) no competition with agonists, (ii) voltage dependence, and (iii) use dependence. Significantly, NBTA protects rodent hippocampal neurons from NMDA receptor, but not kainate receptor-mediated excitotoxic cell death, in agreement with its selective action on the corresponding recombinant receptors. Mutagenesis data indicate that the N site, a key asparagine on the M2 transmembrane segment of the NR1 subunit, is the main determinant of the blocker action. The results highlight the potential of this compound as a neuroprotectant.
Albright,
Neural science: a century of progress and the mysteries that remain.
2000, Pubmed
Albright,
Neural science: a century of progress and the mysteries that remain.
2000,
Pubmed
Beck,
NMDAR channel segments forming the extracellular vestibule inferred from the accessibility of substituted cysteines.
1999,
Pubmed
,
Xenbase
Chase,
Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications.
2000,
Pubmed
Chen,
Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism.
1997,
Pubmed
Choi,
The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death.
1990,
Pubmed
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Dörner,
The synthesis of peptidomimetic combinatorial libraries through successive amide alkylations.
1996,
Pubmed
Feher,
A simple model for the prediction of blood-brain partitioning.
2000,
Pubmed
Ferrer-Montiel,
Selected peptides targeted to the NMDA receptor channel protect neurons from excitotoxic death.
1998,
Pubmed
,
Xenbase
Ferrer-Montiel,
Structural determinants of the blocker binding site in glutamate and NMDA receptor channels.
1998,
Pubmed
,
Xenbase
Ferrer-Montiel,
Engineering the NMDA receptor channel lining.
1999,
Pubmed
Frankiewicz,
Effects of memantine and MK-801 on NMDA-induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices.
1996,
Pubmed
Gill,
Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil.
1987,
Pubmed
Heintz,
Insights from mouse models into the molecular basis of neurodegeneration.
2000,
Pubmed
Houghten,
Mixture-based synthetic combinatorial libraries.
1999,
Pubmed
Houghten,
General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids.
1985,
Pubmed
Houghten,
Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery.
1991,
Pubmed
Huettner,
Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels.
1988,
Pubmed
Igarashi,
Benzyl-polyamines: novel, potent N-methyl-D-aspartate receptor antagonists.
1997,
Pubmed
,
Xenbase
Kuner,
Structure of the NMDA receptor channel M2 segment inferred from the accessibility of substituted cysteines.
1996,
Pubmed
,
Xenbase
Le Bourdellès,
Cloning, functional coexpression, and pharmacological characterisation of human cDNAs encoding NMDA receptor NR1 and NR2A subunits.
1994,
Pubmed
,
Xenbase
Lee,
The changing landscape of ischaemic brain injury mechanisms.
1999,
Pubmed
Muir,
Clinical experience with excitatory amino acid antagonist drugs.
1995,
Pubmed
Olney,
MK-801 prevents hypobaric-ischemic neuronal degeneration in infant rat brain.
1989,
Pubmed
Opella,
Structures of the M2 channel-lining segments from nicotinic acetylcholine and NMDA receptors by NMR spectroscopy.
1999,
Pubmed
Pardridge,
Blood-brain barrier biology and methodology.
1999,
Pubmed
Parsons,
Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics: in vitro and in vivo characterization.
1999,
Pubmed
,
Xenbase
Planells-Cases,
Molecular cloning, functional expression, and pharmacological characterization of an N-methyl-D-aspartate receptor subunit from human brain.
1993,
Pubmed
,
Xenbase
Pringle,
Neuroprotection by both NMDA and non-NMDA receptor antagonists in in vitro ischemia.
1997,
Pubmed
Schinder,
Mitochondrial dysfunction is a primary event in glutamate neurotoxicity.
1996,
Pubmed
Simon,
Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain.
1984,
Pubmed
Sun,
Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors.
1992,
Pubmed
,
Xenbase
Villarroel,
Dimensions of the narrow portion of a recombinant NMDA receptor channel.
1995,
Pubmed
,
Xenbase
Williams,
The selectivity filter of the N-methyl-D-aspartate receptor: a tryptophan residue controls block and permeation of Mg2+.
1998,
Pubmed
Winblad,
Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine).
1999,
Pubmed
Wollmuth,
Differential contribution of the NR1- and NR2A-subunits to the selectivity filter of recombinant NMDA receptor channels.
1996,
Pubmed
,
Xenbase
Wollmuth,
Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the voltage-dependent block by extracellular Mg2+.
1998,
Pubmed
,
Xenbase
Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed