Na v 1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents

• Type of Material: Article
• Authors: Frank Bosmans, Johns Hopkins University; John Gilchrist, Johns Hopkins University; Stacey Dutton, Emory University; Marcelo Diaz-Bustamante, Johns Hopkins University; Annie McPherson, Emory University; Nicolas Olivares, Johns Hopkins University; Jeet Kalia, Indian Institute of Science Education and Research Pune; Andrew Escayg, Emory University
• Language: English
• Date: 2014-05-16
• Publisher: American Chemical Society
• Publication Version: Final Published Version
• Copyright Statement: © 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
• Final Published Version (URL): http://dx.doi.org/10.1021/cb500108p
• Title of Journal or Parent Work: ACS Chemical Biology
• ISSN: 1554-8929
• Volume: 9
• Issue: 5
• Start Page: 1204
• End Page: 1212
• Research Categories: Biology, Genetics; Health Sciences, General

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.