Na_v1.1 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.

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

“…Moreover, Na v 1.1 expression in other regions of the brain may contribute to Hm1a toxicity (4). Nonetheless, our Na v 1.1 inactivation gating model provides a rationale for developing new Na v 1.1-selective agents with a greater safety margin (11). For example, a VSDIV-binding compound that equally favors the resting and activated voltage sensor over a subsequent slowinactivation-coupled state should prevent Na v 1.1 accumulation in the slow inactivated state without introducing persistent current.…”

“…Human Na v 1.1 was obtained from Origene Technologies and modified as reported previously (11). Rat Na v 1.4 was a gift from Baron Chanda, University of Wisconsin-Madison.…”

“…A high degree of amino acid sequence similarity among Na v channels complicates the development of subtype-selective pharmacologic agents, however (11). In addition, an efficacious Na v 1.1 compound should target the appropriate gating transition to restore normal excitability patterns within a particular tissue.…”

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant

“…Each mouse was manually restrained during corneal stimulation (6 Hz, 0.2-ms pulse, 3 s) using a constant current device (ECT Unit 57800; Ugo Basile, Comerio, Italy). Behavioral seizures were scored based on a modified Racine Scale (RS): RS0 = no abnormal behavior; RS1 = immobile for ≥3 s, then resumption of normal behavior; RS2 = forelimb clonus, paw waving; RS3 = generalized tonic-clonic seizure with rearing and falling 31 . Male mice were tested at three current intensities: 18 mA ( N = 11–16/group), 22 mA ( N = 16–22/group), and 27 mA ( N = 16–22/group) with a one-week recovery between each test session.…”

Synthesis and Anti-Inflammatory Activity Evaluation of 5-(1-Benzyl-1H-[1,2,3]Triazol-4-yl)-4-Phenyl- 4H-[1,2,4]Triazole-3-Thiol Derivatives

“…9 It was reported that triazole compounds exhibited kinds of pharmacological abilities, such as anti-inflammatory, analgesic, antinociceptive, antiepileptic etc. [10][11][12][13][14][15][16] 1,2,3-Triazole and 1,2,4-triazole all possess anti-inflammatory activity. [11][12][13]16 In order to search new compounds with higher anti-inflammatory activities and lower toxicity, 1,2,3-triazole and 1,2,4-triazole derivatives were designed on the basis of association principle.…”