PubMed 24635129

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1 , Nav1.1 , Nav1.2 , Nav1.3 , Nav1.6

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

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

Journal, date & volume: ACS Chem. Biol., 2014 May 16 , 9, 1204-12

PubMed link:

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.