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On the Process of Finding Novel and Selective Sodium Channel Blockers for the Treatment of Diseases

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Ion Channels

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 3))

Abstract

Blockers of voltage-gated sodium channels have several therapeutic uses, including use as anticonvulsants, antiarrhythmics, and analgesics. However, voltage-gated sodium channels are challenging drug targets, and most of the clinically used drugs were found before their sodium channel blocking mechanism was known. Sodium channels are a family of ten homologous subtypes, and family members are expressed differentially throughout the nervous system and in cardiac and skeletal muscle tissue. They exist in closed, open, and inactivated conformational states, and selective interactions with one or more of these states differentiates therapeutically useful drugs from neurotoxins. Therefore, assays used in drug discovery need to be sensitive to these mechanisms of action and preferably able to distinguish between drug interactions with different conformational states. Electrophysiological assays are ideally suited for this task, and the recent development of automated electrophysiology instrumentation affords medium throughput. Higher capacity assays amenable to studying sodium channel pharmacology include ligand binding, flux, and fluorescent assays.

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  1. Dept. of Ion Channels, Merck Research Laboratories, Mail Code RY80N-C31, P.O. Box 2000, 07065, Rahway, NJ, USA

    Birgit T. Priest

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Bernard Fermini Birgit T. Priest

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Priest, B.T. (2008). On the Process of Finding Novel and Selective Sodium Channel Blockers for the Treatment of Diseases. In: Fermini, B., Priest, B.T. (eds) Ion Channels. Topics in Medicinal Chemistry, vol 3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2008_019

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