E-4031 acts on a specific class ofvoltage-gated potassium channels mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate theIKr current, which repolarizes the myocardial cells.[3][4] The hERG channel is encoded by ether-a-go-go related gene (hERG).[5]
E-4031 blocks hERG-type potassium channels[5][6] by binding to the open channels.[7] Its structural target within the hERG-channel is unclear, but some other methanesulfonanilide class III antiarrhythmic drugs are known to bind to the S6 domain orC-terminal of the hERG-channel.[8][9][10][11][12][13]
Reducing IKr in myocardial cells prolongs thecardiac action potential and thus prolongs theQT-interval.[7][14] In non-cardiac cells, blocking Ikr has a different effect: it increases the frequency of action potentials.[5]
E-4031 is solely used for research purposes. So far, oneclinical trial has been conducted to test the effect of E-4031 on prolongation of theQT-interval.[15]
^Kim I, Boyle KM, Carroll JL (April 2005). "Postnatal development of E-4031-sensitive potassium current in rat carotid chemoreceptor cells".Journal of Applied Physiology.98 (4):1469–77.doi:10.1152/japplphysiol.01254.2003.PMID15591286.
^Oinuma H, Miyake K, Yamanaka M, Nomoto K, Katoh H, Sawada K, Shino M, Hamano S (March 1990). "4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents".Journal of Medicinal Chemistry.33 (3):903–5.doi:10.1021/jm00165a003.PMID2308138.
^Gerlach AC, Stoehr SJ, Castle NA (January 2010). "Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574)".Molecular Pharmacology.77 (1):58–68.doi:10.1124/mol.109.059543.PMID19805508.S2CID20582680.
^abcWeinsberg F, Bauer CK, Schwarz JR (1997). "The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumour cells (GH3/B6 cells)".Pflügers Archiv.434 (1):1–10.doi:10.1007/s004240050356.PMID9094250.S2CID10233500.
^abSpector PS, Curran ME, Keating MT, Sanguinetti MC (March 1996). "Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides".Circulation Research.78 (3):499–503.doi:10.1161/01.res.78.3.499.PMID8593709.
^Lees-Miller JP, Duan Y, Teng GQ, Duff HJ (February 2000). "Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites".Molecular Pharmacology.57 (2):367–74.doi:10.1016/S0026-895X(24)23209-0.PMID10648647.
^Sănchez-Chapula JA, Ferrer T, Navarro-Polanco RA, Sanguinetti MC (May 2003). "Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain".Molecular Pharmacology.63 (5):1051–8.doi:10.1124/mol.63.5.1051.PMID12695533.
^abPerry M, de Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, Mitcheson J (August 2004). "Structural determinants of HERG channel block by clofilium and ibutilide".Molecular Pharmacology.66 (2):240–9.doi:10.1124/mol.104.000117.PMID15266014.S2CID7974939.
^Wettwer E, Grundke M, Ravens U (November 1992). "Differential effects of the new class III antiarrhythmic agents almokalant, E-4031 and D-sotalol, and of quinidine, on delayed rectifier currents in guinea pig ventricular myocytes".Cardiovascular Research.26 (11):1145–52.doi:10.1093/cvr/26.11.1145.PMID1291093.
^Okada Y, Ogawa S, Sadanaga T, Mitamura H (January 1996). "Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour Holter electrocardiography".Journal of the American College of Cardiology.27 (1):84–9.doi:10.1016/0735-1097(95)00424-6.PMID8522715.
