E-4031 dihydrochloride

E-4031 dihydrochloride is a methanesulfonanilide class Ⅲ antiarrhythmic agent, capable of prolonging cardiac action potential duration by blocking members of the ether-a-go-go-related gene (ERG) K⁺ channel family (IC50 = 29 nM). E-4031 dihydrochloride inhibits a variety of ERG isoforms, with K_D values being 99, 116 and 193 nM for ERG1, ERG2 and ERG3, respectively. Voltage-gated potassium ERG channels regulate the inwardly rectifying K⁺ current that repolarizes myocardial cells, gut smooth muscle cells, as well as interstitial cells of Cajal. E-4031 dihydrochloride, as a human ERG (hERG; also known as Kv11.1) K⁺ channel blocker, has been used to pharmacologically rescue misprocessed hERG mutations in the long QT syndrome type 2.

References:

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2. Shi W, Wymore RS, Wang HS, et al. Identification of two nervous system-specific members of the erg potassium channel gene family. Journal of Neuroscience, 1997, 17(24): 9423-9432.

3. White EJ, Park SJ, Foster JA, et al. Ether-a-go-go-related gene 3 is the main candidate for the E-4031-sensitive potassium current in the pacemaker interstitial cells of Cajal. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008, 295(4): G691-699.

4. Ficker E, Obejero-Paz CA, Zhao S, et al. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. Journal of Biological Chemistry, 2002, 277(7): 4989-4998.

5. Fujiki A. Electrophysiological effects of E-4031, a novel class Ⅲ antiarrhythmic agent. Cardiovascular Drun Reviews, 1994, 12(2): 165-172.