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Na(v)1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents
[Image: see text] Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027953/ https://www.ncbi.nlm.nih.gov/pubmed/24635129 http://dx.doi.org/10.1021/cb500108p |
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author | Gilchrist, John Dutton, Stacey Diaz-Bustamante, Marcelo McPherson, Annie Olivares, Nicolas Kalia, Jeet Escayg, Andrew Bosmans, Frank |
author_facet | Gilchrist, John Dutton, Stacey Diaz-Bustamante, Marcelo McPherson, Annie Olivares, Nicolas Kalia, Jeet Escayg, Andrew Bosmans, Frank |
author_sort | Gilchrist, John |
collection | PubMed |
description | [Image: see text] Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Na(v)) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Na(v)1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNa(v)1.1. Subsequent structure–activity relationship experiments with related N-benzyl triazole compounds on four brain hNa(v) channel isoforms revealed a novel drug variant that (1) shifts hNa(v)1.1 opening to more depolarized voltages without further alterations in the gating properties of hNa(v)1.1, hNa(v)1.2, hNa(v)1.3, and hNa(v)1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Na(v) channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Na(v) channel isoforms while limiting adverse effects. |
format | Online Article Text |
id | pubmed-4027953 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-40279532015-03-17 Na(v)1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents Gilchrist, John Dutton, Stacey Diaz-Bustamante, Marcelo McPherson, Annie Olivares, Nicolas Kalia, Jeet Escayg, Andrew Bosmans, Frank ACS Chem Biol [Image: see text] Here, we report the discovery of a novel anticonvulsant drug with a molecular organization based on the unique scaffold of rufinamide, an anti-epileptic compound used in a clinical setting to treat severe epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating evidence supports a working mechanism through voltage-gated sodium (Na(v)) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Na(v)1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNa(v)1.1. Subsequent structure–activity relationship experiments with related N-benzyl triazole compounds on four brain hNa(v) channel isoforms revealed a novel drug variant that (1) shifts hNa(v)1.1 opening to more depolarized voltages without further alterations in the gating properties of hNa(v)1.1, hNa(v)1.2, hNa(v)1.3, and hNa(v)1.6; (2) increases the threshold to action potential initiation in hippocampal neurons; and (3) greatly reduces the frequency of seizures in three animal models. Altogether, our results provide novel molecular insights into the rational development of Na(v) channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Na(v) channel isoforms while limiting adverse effects. American Chemical Society 2014-03-17 2014-05-16 /pmc/articles/PMC4027953/ /pubmed/24635129 http://dx.doi.org/10.1021/cb500108p Text en Copyright © 2014 American Chemical Society |
spellingShingle | Gilchrist, John Dutton, Stacey Diaz-Bustamante, Marcelo McPherson, Annie Olivares, Nicolas Kalia, Jeet Escayg, Andrew Bosmans, Frank Na(v)1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents |
title | Na(v)1.1 Modulation by a Novel Triazole Compound
Attenuates Epileptic Seizures in Rodents |
title_full | Na(v)1.1 Modulation by a Novel Triazole Compound
Attenuates Epileptic Seizures in Rodents |
title_fullStr | Na(v)1.1 Modulation by a Novel Triazole Compound
Attenuates Epileptic Seizures in Rodents |
title_full_unstemmed | Na(v)1.1 Modulation by a Novel Triazole Compound
Attenuates Epileptic Seizures in Rodents |
title_short | Na(v)1.1 Modulation by a Novel Triazole Compound
Attenuates Epileptic Seizures in Rodents |
title_sort | na(v)1.1 modulation by a novel triazole compound
attenuates epileptic seizures in rodents |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027953/ https://www.ncbi.nlm.nih.gov/pubmed/24635129 http://dx.doi.org/10.1021/cb500108p |
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