The Riluzole Derivative 2-Amino-6-trifluoromethylthio-benzothiazole (SKA-19), a Mixed K<inf>Ca</inf>2 Activator and Na<inf>V</inf> Blocker, is a Potent Novel Anticonvulsant

Nichole Coleman, Hai M. Nguyen, Zhengyu Cao, Brandon M. Brown, David Paul Jenkins, Dorota Zolkowska, Yi Je Chen, Brian S. Tanaka, Alan L. Goldin, Michael A. Rogawski, Isaac N. Pessah, Heike Wulff

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Inhibitors of voltage-gated sodium channels (Na<inf>v</inf>) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent Na<inf>V</inf> channel blocker and an activator of small-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED<inf>50</inf> 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED<inf>50</inf> 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED<inf>50</inf> 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED<inf>50</inf> 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED<inf>50</inf> 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD<inf>50</inf>/ED<inf>50</inf>) of 6–9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects Na<inf>V</inf> and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Na<inf>v</inf> channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

Original languageEnglish (US)
Pages (from-to)234-249
Number of pages16
JournalNeurotherapeutics
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Afterhyperpolarization
  • Anticonvulsant
  • Calcium-activated potassium channel
  • Riluzole
  • Seizure models
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Clinical Neurology
  • Pharmacology

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