Isoform Selective Voltage-Gated Sodium Channel Modulators and the Therapy of Pain

Marko      Jukic; Danijel      Kikelj; Marko      Anderluh

Abstract

Voltage-gated sodium channels are large transmembrane protein complexes responsible for the propagation and transmission of electrical impulses through nerve, muscle and endocrine cells and cell systems. Dysregulated expression and/or functional changes of ion channel isoforms are found in many associated pathological conditions. In such cases, modulation of voltage gated sodium channels (Na_V channels) is a recognised approach in medicinal chemistry. Multiple small-molecule active compounds are used for a plethora of Na_V channel-linked indications, for example epilepsy and CNS disorders, arrhythmia, stroke and pain states such as congenital analgesia/hyperalgesia and neuropathic pain. As existent Na_V channel modulators suffer mainly from selectivity issues and thus exert significant side effects, novel and selective Na_V channel modulators would be beneficial. Consequently, the increased research on voltage-gated sodium channels has led to a large number of novel compounds that exploit classic binding site selectivity with state-dependence or functional selectivity. Such compounds offer selective targeting and new possibilities for studying the physiology of Na_V channels and pathophysiology of the associated ailment conditions. This review consolidates the recent literature on Na_V 1.3, 1.7 and 1.8 channel isoform selective and/or state-dependent modulators. In particular, their structure-activity relationship is illustrated, especially in the context of selectivity on a particular isoform, and their applicability in the therapy of neuropathic pain is described.

Keywords: Isoform selective inhibitors, Na_V 1.3, Na_V 1.7, Na_V 1.8, neuropathic pain, state-dependent inhibitors, therapy of pain, voltage-gated sodium channels.