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

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Neurotherapeutics

Abstract

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 NaV channel 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 (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 NaV 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 Nav channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

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Acknowledgments

This work was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), grant numbers U54NS079202 and R21NS072585. N.C. was supported by a National Heart, Lung & Blood Institute T32 Training Program in Basic and Translational Cardiovascular Science (T32HL086350). B.M.B. was supported by a National Institute of General Medical Sciences-funded Pharmacology Training Program (T32GM099608). We are further highly indebted to the NIH Anticonvulsant Screening program. This work would not have been possible without their help.

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  1. Department of Pharmacology, Genome and Biomedical Sciences Facility, School of Medicine, University of California, 451 Health Sciences Drive, Davis, CA, 95616, USA

    Nichole Coleman, Hai M. Nguyen, Brandon M. Brown, David Paul Jenkins, Yi-Je Chen & Heike Wulff

  2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China

    Zhengyu Cao

  3. Department of Neurology, School of Medicine, University of California, Davis, CA, USA

    Dorota Zolkowska & Michael A. Rogawski

  4. Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA

    Brian S. Tanaka & Alan L. Goldin

  5. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA

    Isaac N. Pessah

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Correspondence to Heike Wulff.

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N.C. and H.M.N. contributed equally to this work.

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Coleman, N., Nguyen, H.M., Cao, Z. et al. The Riluzole Derivative 2-Amino-6-trifluoromethylthio-benzothiazole (SKA-19), a Mixed KCa2 Activator and NaV Blocker, is a Potent Novel Anticonvulsant. Neurotherapeutics 12, 234–249 (2015). https://doi.org/10.1007/s13311-014-0305-y

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