E-4031 acts on a specific class of
voltage-gated potassium channels mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate the
IKr current, which repolarizes the myocardial cells.[3][4] The hERG channel is encoded by ether-a-go-go related gene (hERG).[5]
Mode of action
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 or
C-terminal of the hERG-channel.[8][9][10][11][12][13]
Reducing IKr in myocardial cells prolongs the
cardiac action potential and thus prolongs the
QT-interval.[7][14] In non-cardiac cells, blocking Ikr has a different effect: it increases the frequency of action potentials.[5]
Toxicity
As E-4031 can prolong the QT-interval, it can cause lethal
arrhythmias.[13]
Therapeutic use
E-4031 is solely used for research purposes. So far, one
clinical trial has been conducted to test the effect of E-4031 on prolongation of the
QT-interval.[15]
References
^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.
^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.
E-4031 acts on a specific class of
voltage-gated potassium channels mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate the
IKr current, which repolarizes the myocardial cells.[3][4] The hERG channel is encoded by ether-a-go-go related gene (hERG).[5]
Mode of action
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 or
C-terminal of the hERG-channel.[8][9][10][11][12][13]
Reducing IKr in myocardial cells prolongs the
cardiac action potential and thus prolongs the
QT-interval.[7][14] In non-cardiac cells, blocking Ikr has a different effect: it increases the frequency of action potentials.[5]
Toxicity
As E-4031 can prolong the QT-interval, it can cause lethal
arrhythmias.[13]
Therapeutic use
E-4031 is solely used for research purposes. So far, one
clinical trial has been conducted to test the effect of E-4031 on prolongation of the
QT-interval.[15]
References
^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.
^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.