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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Blondelle, S. E. Ostresh, J. M. Montal, M. Houghten, R. A. Tai, K. K. |
| Description | Author Affiliation: Tai KK ( Section of Neurobiology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366, USA.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 6 |
| Volume Number | 98 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2001-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Amines Pharmacology Neurons Drug Effects Neuroprotective Agents Receptors, N-Methyl-D-Aspartate Antagonists & Inhibitors Animals Cell Death Cells, Cultured Hippocampus Cytology Genetics Xenopus Laevis Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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