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Effects of Benzothiazolamines on Voltage-Gated Sodium Channels

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Voltage-gated Sodium Channels: Structure, Function and Channelopathies

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 246))

Abstract

Benzothiazole is a versatile fused heterocycle that aroused much interest in drug discovery as anticonvulsant, neuroprotective, analgesic, anti-inflammatory, antimicrobial, and anticancer. Two benzothiazolamines, riluzole and lubeluzole, are known blockers of voltage-gated sodium (Nav) channels. Riluzole is clinically used as a neuroprotectant in amyotrophic lateral sclerosis. Inhibition of Nav channels by riluzole is voltage-dependent due to preferential binding to inactivated sodium channels. Yet the drug exerts little use-dependent block, probably because it lacks protonable amine. One important property is riluzole ability to inhibit persistent Na+ currents, which likely contributes to its neuroprotective activity. Lubeluzole showed promising neuroprotective effects in animal stroke models, but failed to show benefits in acute ischemic stroke in humans. One important concern is its propensity to prolong the cardiac QT interval, due to hERG K+ channel block. Lubeluzole very potently inhibits Nav channels in a voltage- and use-dependent manner, due to its great preferential affinity for inactivated channels and the presence of a protonable amine group. Patch-clamp experiments suggest that the binding sites of both drugs overlap the local anesthetic receptor within the ion-conducting pathway. Riluzole and lubeluzole displayed very potent antimyotonic activity in a rat model of myotonia, a pathological skeletal muscle condition characterized by high-frequency runs of action potentials. Such results well support the repurposing of riluzole as an antimyotonic drug, allowing the launch of a pilot study in myotonic patients. Riluzole, lubeluzole, and new Nav channel blockers built on the benzothiazolamine scaffold will certainly continue to be investigated for possible clinical applications.

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Acknowledgments

This study was supported by grant #19027 from A.F.M. (Association Française contre les Myopathies).

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  1. Section of Pharmacology, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Policlinico, Piazza G. Cesare 11, 70124, Bari, Italy

    Alessandro Farinato, Concetta Altamura & Jean-François Desaphy

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  1. Alessandro Farinato
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  2. Concetta Altamura
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  3. Jean-François Desaphy
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Correspondence to Jean-François Desaphy .

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  1. CERVO Brain Research Center, Institut Universitaire en Santé Mentale, Quebec, Canada

    Mohamed Chahine

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Farinato, A., Altamura, C., Desaphy, JF. (2017). Effects of Benzothiazolamines on Voltage-Gated Sodium Channels. In: Chahine, M. (eds) Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Handbook of Experimental Pharmacology, vol 246. Springer, Cham. https://doi.org/10.1007/164_2017_46

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