Recent advances in the medicinal chemistry of sodium channel blockers and their therapeutic potential.
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 VGSC isoforms have been identified and have a distinct pattern of expression within the human body. In addition, VGSCs also have distinct electrophysiological profiles with differing activation and inactivation states. As such, there is a concerted effort to develop not only isoform selective antagonists, but also antagonists that exhibit state selectivity, particularly to the inactivated state of the channel. This review will provide a brief historical prospective and will primarily focus on recent advances in the development of isoform specific and state selective sodium channel antagonists and the medicinal chemistry involved, surveying the emerging therapeutic fields.
Dipartimento Farmaceutico, Universitá degli Studi di Parma, V.le G.P. Usberti, 27/A, I-43100 Parma, Italy. valentina.zuliani@unipr.it
Valentina
V
Zuliani
Manoj K
MK
Patel
Marco
M
Fantini
Mirko
M
Rivara
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006801:Humans; D020033:Protein Isoforms; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D020033:Protein Isoforms; D026941:Sodium Channel Blockers; D015222:Sodium Channels