title: Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents.
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.
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: John
authors.initials: J
authors.lastname: Gilchrist
authors.forename: Stacey
authors.initials: S
authors.lastname: Dutton
authors.forename: Marcelo
authors.initials: M
authors.lastname: Diaz-Bustamante
authors.forename: Annie
authors.initials: A
authors.lastname: McPherson
authors.forename: Nicolas
authors.initials: N
authors.lastname: Olivares
authors.forename: Jeet
authors.initials: J
authors.lastname: Kalia
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
authors.forename: Frank
authors.initials: F
authors.lastname: Bosmans
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D055808:Drug Discovery; D004827:Epilepsy / Q000188:drug therapy*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; D014230:Triazoles; C079703:rufinamide