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Chemical Compound Review

Tocris-1808     N-[4-[[1-[2-(6-methylpyridin- 2-yl)ethyl]-4...

Synonyms: CHEMBL327980, SureCN2168557, BSPBio_001313, KBioGR_000033, KBioSS_000033, ...
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Disease relevance of Tocris-1808

  • RESULTS: The I(Kr) block (E-4031: 1 micromol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias [1].
  • E-4031 prolonged the refractory period during atrial flutter to 129 +/- 6 ms, which did not differ significantly from the flutter cycle length immediately before termination (134 +/- 4 ms) [2].
  • CONCLUSION: These results suggest that E-4031 has a potential effect in the treatment of human paroxysmal atrial fibrillation [3].
  • Electrophysiologic effects of E-4031, a class III antiarrhythmic agent, on re-entrant ventricular arrhythmias in a canine 7-day-old myocardial infarction model [4].
  • E-4031 reduced the severity of arrhythmias from sustained ventricular tachycardia (VT) to nonsustained VT (7 dogs at 1.0 mg/kg, P = .013 vs. vehicle) [5].

High impact information on Tocris-1808

  • Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031 [6].
  • APD was reduced by >3-fold in E3-transduced cells relative to controls, while E-4031-insensitive I(K) and activation kinetics were significantly augmented [7].
  • METHODS AND RESULTS: Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 mumol/L)-induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques [8].
  • Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes [9].
  • Ventricular myocytes isolated from adult wild-type hearts consistently exhibited an inwardly rectifying E-4031-sensitive K+ current resembling the rapidly activating cardiac delayed rectifier K+ current (Ikr) in its time and voltage dependence; this current was not found in cells isolated from G628S mice [10].

Chemical compound and disease context of Tocris-1808


Biological context of Tocris-1808

  • In isolated left atria, d,l-sotalol (100 mumol/L), E-4031 (3 mumol/L), and MS-551 (30 mumol/L) partially reversed the carbachol-induced action potential shortening [8].
  • The effect of E-4031 on HERG protein trafficking was concentration-dependent and required low drug concentrations (saturation present at 5 microM), developed rapidly with drug exposure, and occurred post-translationally [15].
  • One current was specifically blocked by the benzenesulfonamide antiarrhythmic agent, E-4031 (IC50 = 397 nM) [16].
  • E-4031-sensitive currents (IKr) reached a maximum at a membrane potential of -10 mV and showed pronounced inward rectification at more-positive membrane potentials [17].
  • When cervical vagus stimulation decreased the heart rate, RA dP/dt and RV +dP/dt and prolonged the AV conduction time, E-4031 antagonized the negative chronotropic response in a dose-dependent manner but affected neither dromotropic nor atrial inotropic responses [18].

Anatomical context of Tocris-1808

  • E-4031 (1 microM) increased RP by 50% with no effect on contractile force in papillary muscles isolated from guinea pig heart [19].
  • Class III antiarrhythmic drugs such as E-4031 and MK-499 are potent and specific blockers of I (Kr) in cardiac myocytes [20].
  • Consistent with initial findings, 1 micromol/L MK-499 and E-4031 had not effect on HERG when oocytes were voltage clamped at a negative potential and not pulsed during equilibration with the drug [20].
  • We previously reported that the N470D mutation is retained in the endoplasmic reticulum (ER) but can be rescued to the plasma membrane by hERG channel blocker E-4031 [21].
  • The selective HERG channel blocker, E-4031, reduced proliferation of CEM, U937, and K562 cells, and this appears to be the first direct evidence of a functional role for the HERG current in cancer cells [22].

Associations of Tocris-1808 with other chemical compounds


Gene context of Tocris-1808

  • Low concentrations of the KCNH2 blockers E-4031 (10(-8) M) and MK-499 (3 x 10(-8) M) increased phasic contractile amplitude and the number of spikes per slow wave [27].
  • Melk2 currents are insensitive to E-4031, a class III antiarrhythmic compound that blocks the Human Ether-à-go-go-Related Gene (HERG) channel and its counterpart in native tissues, IKr [28].
  • The influence of ERG on insulin secretion was monitored by perfusion of rat INS-1 beta-cells with the blockers E-4031 and rBeKm-1.We identified Erg1a, Erg1b, Erg2 and Erg3 transcripts in islets and INS-1 cells [29].
  • The membrane depolarization by 1 microM E-4031 indicates the contribution of K(+) channels encoded by ERG1/KCNE2 to the resting membrane potential in stomach SMCs [30].
  • These results suggest that defective folding of N470D contributes to its prolonged association with calnexin and ER retention and that E-4031 may restore proper folding of the N470D channel leading to its cell surface expression [21].

Analytical, diagnostic and therapeutic context of Tocris-1808

  • Block of the delayed rectifier potassium current, IK, by the class IC antiarrhythmic agent, flecainide, and by the novel selective class III antiarrhythmic agent, E-4031, were compared in isolated cat ventricular myocytes using the single suction-pipette, voltage-clamp technique [9].
  • A dose of 100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the control group, except for one rabbit (1 of 10) [31].
  • METHODS: Action potentials and whole-cell currents were measured in isolated guinea pig ventricular myocytes with a patch clamp procedure during perfusion of normotonic, normotonic with addition of E-4031, and hypotonic plus E-4031 solutions [32].
  • The induction of sustained ventricular tachycardia by programmed electrical stimulation was not suppressed by i.v. infusion of E-4031 at 1 microgram/kg/min, but was suppressed markedly by infusion at 10 micrograms/kg/min in six of seven dogs [4].
  • Measurements of basal prolactin secretion with the reverse hemolytic plaque assay showed that the number of prolactin secreting cells and the amount of prolactin secreted from single lactotrophs was significantly increased in the presence of E-4031 [33].


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  12. Antiarrhythmic drugs preferentially produce conduction block at the area of slow conduction in the re-entrant circuit of canine atrial flutter: comparative study of disopyramide, flecainide, and E-4031. Inoue, H., Yamashita, T., Usui, M., Nozaki, A., Sugimoto, T. Cardiovasc. Res. (1991) [Pubmed]
  13. Effects of antiarrhythmic agents classified as class III group on ischaemia-induced myocardial damage in canine hearts. Sano, T., Sugiyama, S., Taki, K., Hanaki, Y., Shimada, Y., Ozawa, T. Br. J. Pharmacol. (1990) [Pubmed]
  14. Diabetes mellitus reduces the antiarrhythmic effect of ion channel blockers. Ito, I., Hayashi, Y., Kawai, Y., Iwasaki, M., Takada, K., Kamibayashi, T., Yamatodani, A., Mashimo, T. Anesth. Analg. (2006) [Pubmed]
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