Ion Channels and Their Inhibitors

Abstract

The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability. Abnormal activity of sodium channels is related to several pathological processes, including cardiac arrhythmias, epilepsy, chronic pain, neurodegenerative diseases, and spasticity. In view of this, VGSCs are considered important therapeutic targets for the treatment of these disorders. To date, nine functional VGSC isoforms have been identified and have a distinct pattern of expression within the human body. In addition, VGSC also have distinct electrophysiological profiles with differing activation and inactivation states. As such, there is a concerted effort to develop not only isoform selective blockers, but also blockers that exhibit state selectivity, particularly to the inactivated state of the channel. This article provides a brief historical perspective and primarily focuses on recent advances in the development of isoform specific and state selective sodium channel blockers and the medicinal chemistry involved, surveying the emerging therapeutic fields.