title: The riluzole derivative 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a mixed KCa2 activator and NaV blocker, is a potent novel anticonvulsant.
abstract: Inhibitors of voltage-gated sodium channels (Na(v)) 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 NaV channel blocker and an activator of small-conductance Ca(2+)-activated K(+) 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 (ED50 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED50 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED50 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED50 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED50 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD50/ED50) 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(V) 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(v) channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.
authors.affiliation: Department of Pharmacology, Genome and Biomedical Sciences Facility, School of Medicine, University of California, 451 Health Sciences Drive, Davis, CA, 95616, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Coleman
authors.forename: Hai M
authors.initials: HM
authors.lastname: Nguyen
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Brown
authors.forename: David Paul
authors.initials: DP
authors.lastname: Jenkins
authors.forename: Dorota
authors.initials: D
authors.lastname: Zolkowska
authors.forename: Yi-Je
authors.initials: YJ
authors.lastname: Chen
authors.forename: Brian S
authors.initials: BS
authors.lastname: Tanaka
authors.forename: Alan L
authors.initials: AL
authors.lastname: Goldin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rogawski
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D061566:Voltage-Gated Sodium Channels; D019782:Riluzole