An N-Methyl-D-Aspartate Receptor Channel Blocker with Neuroprotective Activity

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 neur...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-03, Vol.98 (6), p.3519-3524
Main Authors: Tai, Kwok-Keung, Blondelle, Sylvie E., Ostresh, John M., Houghten, Richard A., Montal, Mauricio
Format: Article
Language:English
Subjects:
Amines - pharmacology
Amino acids
Animals
Biological Sciences
Cell Death
Cells, Cultured
Channel blockers
Electric current
Female
Hippocampus - cytology
Inhibitory concentration 50
Libraries
N methyl D aspartate receptors
N-Benzylated triamine
Nervous system
Neurology
Neurons
Neurons - cytology
Neurons - drug effects
Neuroprotectants
Neuroprotective Agents - pharmacology
Oocytes
Receptors
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - genetics
Toxicity
Xenopus laevis
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Summary: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 IC50 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.061449498