Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents

John Gilchrist, Stacey Dutton, Marcelo Diaz-Bustamante, Annie McPherson, Nicolas Olivares, Jeet Kalia, Andrew Escayg, Frank Bosmans

Research output: Contribution to journalArticle

Abstract

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 (Nav) channels, we found that a clinically relevant rufinamide concentration inhibits human (h)Nav1.1 activation, a distinct working mechanism among anticonvulsants and a feature worth exploring for treating a growing number of debilitating disorders involving hNav1.1. Subsequent structure-activity relationship experiments with related N-benzyl triazole compounds on four brain hNav channel isoforms revealed a novel drug variant that (1) shifts hNav1.1 opening to more depolarized voltages without further alterations in the gating properties of hNav1.1, hNav1.2, hNav1.3, and hNav1.6; (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 Nav channel-targeting molecules based on the unique rufinamide scaffold, an outcome that may be exploited to design drugs for treating disorders involving particular Nav channel isoforms while limiting adverse effects.

Original languageEnglish (US)
Pages (from-to)1204-1212
Number of pages9
JournalACS chemical biology
Volume9
Issue number5
DOIs
StatePublished - May 16 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Gilchrist, J., Dutton, S., Diaz-Bustamante, M., McPherson, A., Olivares, N., Kalia, J., Escayg, A., & Bosmans, F. (2014). Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents. ACS chemical biology, 9(5), 1204-1212. https://doi.org/10.1021/cb500108p