The Riluzole Derivative 2-Amino-6-trifluoromethylthio-benzothiazole (SKA-19), a Mixed KCa2 Activator and NaVBlocker, is a Potent Novel Anticonvulsant

© 2014, The American Society for Experimental NeuroTherapeutics, Inc. Inhibitors of voltage-gated sodium channels (Nav) 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 NaVchannel blocker and an activator of small-conductance Ca2+-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 (ED501.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED504.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED5012.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED502.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED505.5 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 NaVand 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 Navchannel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.