Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents
Citations Over TimeTop 13% of 2014 papers
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.
Related Papers
- → Gap junction channel gating(2004)309 cited
- → Fast and slow gating of sodium channels encoded by a single mRNA(1990)161 cited
- → K+‐dependent gating of Kir1.1 channels is linked to pH gating through a conformational change in the pore(2001)35 cited
- → Revealing a hidden conducting state by manipulating the intracellular domains in K V 10.1 exposes the coupling between two gating mechanisms(2023)
- → Author Response: Revealing a hidden conducting state by manipulating the intracellular domains in KV10.1 exposes the coupling between two gating mechanisms(2023)