Abstracts

Rationale: Riluzole [2-amino-6-(trifluoromethoxy)benzothiazole], a drug marketed for the treatment of amyotrophic lateral sclerosis, is well recognized to have anticonvulsant properties, with a spectrum of activity in animal models similar to sodium-channel blocking antiepileptic drugs. Accordingly, among its various cellular actions, riluzole inhibits neuronal voltage-gated sodium channels in a use-dependent manner. More recently riluzole has been found to activate apamin-sensitive small-conductance Ca2+-activated KCa2 (SK) channels, which are widely expressed in the nervous system and are responsible for the medium AHP (afterhyperpolarization) that regulates tonic, burst and rhythmic neuronal firing. Riluzole has been used as a template for the design of structurally novel KCa2 activators. Among the KCa2 activators identified by the approach is the sulfur-substituted riluzole analog SKA-19 [2-amino-6-(trifluoromethylthio)benzothiazole], which has KCa2 activating potency comparable to that of riluzole (Sankaranarayanan et al., Mol Pharmacol 2009;75:281-295). SKA-19 was found to have potent anticonvulsant activity in testing conducted by the NINDS Anticonvulsant Screening Program. In the present study, we compared the anticonvulsant activity of riluzole and SKA-19.Methods: The mouse maximal electroshock (MES) and 6 Hz seizure models were used. Motor toxicity was assessed using a modification of the horizontal screen test. ED50 values in the seizure models and TD50 values in the toxicity test were determined by nonlinear fitting of dose-response curves. Stock solutions (5 mg/ml) of riluzole and SKA-19 were prepared in 10% (5 mg/ml) sulfobutylether- -cyclodextrin sodium salts (Captisol ) in 0.9% saline and 5% CremophorEL/95% PBS respectively and diluted further with saline. Drugs solutions were injected intraperitoneally 10 min prior to administration of the electrical stimulus in a volume of 10 ml/kg body weight. Results: Riluzole and SKA-19 were both protective in the MES seizure test with ED50 values of 5.37 and 4.93 mg/kg, respectively. In the 6 Hz test, the ED50 values were 16.36 and 22.54 mg/kg, although these values are uncertain because effective doses cause neurological impairment that precluded a reliable assessment of seizure protection. Although the potency of the two compounds was similar when tested at 10 min in the MES test, SKA-19 (10 mg/kg) had a much more prolonged duration of action. Thus, SKA-19 exhibited protective activity for up to 4 h whereas the duration of activity of riluzole was <1 h. The TD50 values of riluzole and SKA-19 following intraperitoneal administration in solution were 15.77 and 16.33 mg/kg, respectively. Conclusions: Riluzole and SKA-19 exhibit equivalent potency in the MES seizure test but SKA-19 appears to have dramatically improved pharmacokinetic properties. Both compounds have profiles suggesting that seizure protection occurs through a sodium channel blocking mechanism. The extent to which KCa2 activation contributes to seizure protection by these agents remains to be determined.