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Chemical Compound Review

Clofilium     4-(4-chlorophenyl)butyl- diethyl-heptyl...

Synonyms: CHEMBL9484, SureCN157537, AG-G-62481, BSPBio_000318, CHEBI:105583, ...
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Disease relevance of Clofilium

  • In vehicle-pretreated rabbits (n = 19), clofilium invariably induced PVTs, which closely resembled torsade de pointes and were preceded by a marked prolongation of the QTU interval (27 +/- 2.4%, p less than 0.001) [1].
  • In the six animals pretreated with the high dose of P1188 in which no clofilium-induced arrhythmias were elicited, glibenclamide (20 mumol/kg i.v.) was injected after the entire dose of clofilium had been administered [1].
  • Three patients had sustained ventricular tachycardia with programmed stimulation before clofilium infusion; none had more than three repetitive ventricular responses after it [2].
  • In one patient refractoriness of the His-Purkinje system was increased and in two patients atrial fibrillation converted to sinus rhythm after clofilium [2].
  • Clofilium increases atrial and ventricular effective refractory period without changing conduction time and, despite no apparent change in premature ventricular complex frequency, it can abolish the ability to induce ventricular tachycardia by programmed stimulation and is also well tolerated [2].

High impact information on Clofilium

  • Here we show that small Schiff base-forming molecules can substitute for the physiological donor of carbonyl groups and provide a costimulatory signal to CD4 Th-cells through a mechanism that activates clofilium-sensitive K+ and Na+ transport [3].
  • The I(Kr)-specific blockers, E-4031 and dofetilide, do not inhibit KvLQT1, whereas clofilium, a class III antiarrhythmic agent with the propensity to induce torsades de pointes, substantially inhibits the current [4].
  • Clofilium markedly prolonged action potential duration in Purkinje fibers but not in ventricular muscle cells, and eventually, bradycardia-dependent EADs and triggered activity were elicited [1].
  • Anesthetized rabbits were pretreated with propranolol (2 mumol/kg i.v.) and subsequently given a concomitant intravenous infusion of clofilium (63 nmol/kg/min for maximally 15 minutes) and the alpha 1-agonist methoxamine (70 nmol/kg/min) [1].
  • We have studied whether the potassium channel opener pinacidil and two of its pyridylcyanoguanidine analogues (P1075 and P1188) have any antiarrhythmic effects on clofilium-induced PVTs and triggered responses in rabbits in vivo and in vitro [1].

Chemical compound and disease context of Clofilium


Biological context of Clofilium

  • We examined the effect of clofilium, a drug that prolongs cardiac action potential duration without slowing cardiac conduction, on defibrillation energy requirements and ventricular effective refractory periods in a canine model during a 3-week period [10].
  • Intravenous administration of the pyridylcyanoguanidines in doses reducing mean arterial blood pressure by 25 or 50 mm Hg, respectively, was associated with a dose-dependent attenuation in the occurrence of clofilium-induced PVTs [1].
  • HIsK current is totally insensitive to this toxin but is blocked by the antiarrhythmic clofilium (IC50 = 80 microM) [11].
  • In contrast, clofilium, an inhibitor of the KvLQT/IsK potassium channel complex potently inhibited RVD, suggesting a role for the KvLQT/IsK channel complex in cell volume regulation by tracheal epithelial cells [12].
  • In summary, the pore helix residues are important components of the HERG drug binding site, and may be particularly important for drugs with polar substituents, such as a halogen (e.g., clofilium) or a methanesulfonamide (e.g., ibutilide) [13].

Anatomical context of Clofilium

  • While charybdotoxin has no effect on interleukin 2 mRNA induction, clofilium potently inhibits interleukin 2 mRNA expression upon mitogen-induced T cell activation [11].
  • However, when cells were exposed to high apically K(+)/low Na(+) fluid, mimicking endolymph exposure, I(sK)/KvLQT1 actually functioned as a strict apical to basolateral K(+) channel inhibited by clofilium [14].
  • By contrast, in nasal epithelium, the forskolin sensitive chloride secretory current was barely sensitive to XE991 but was sensitive to clofilium [15].
  • The effects of clofilium on single batrachotoxin-activated Na+ channels from rabbit skeletal muscle, incorporated into planar bilayers, were studied under symmetrical 200 mM NaCl conditions [16].
  • These studies focused on the ability of the Class III antiarrhythmic agents bretylium and clofilium to nonspecifically inhibit DHP-receptor binding in canine cardiac sarcolemma [17].

Associations of Clofilium with other chemical compounds

  • Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs [18].
  • 3. Both IK1 and IK2 were sensitive to high concentrations of tetraethylammonium (half-maximal block at approximately 3 mM) and low concentrations of clofilium (half-maximal block by 3-10 microM) [19].
  • The remaining cell conductance was mostly outward and was depressed by acid pH, bupivacaine, methanandamide, quinine, and clofilium, and activated by alkaline pH in a manner consistent with that described for TASK channels [20].
  • Basolateral G(K) was reduced by the K+ channel inhibitors clotrimazole and clofilium, indicating roles for KCNN4 and KCNQ1 in the H2O2-stimulated response [21].
  • 6 Physico-chemical differences of clofilium and the weak base LY97241 determine the access of the drugs to the binding site and thereby the influence of the recording mode on the apparent block potencies [22].

Gene context of Clofilium

  • Clofilium inhibited hEAG1 and hERG1 with the same potency, whereas hEAG2 was about 150-fold less sensitive to this antiarrhythmic agent [23].
  • Moreover, chromanol 293B or clofilium, specific inhibitors of KCNQ1 channels, had no effect on cAMP-dependent I(sc) [24].
  • Enhancement of the Ca2+ response required a 10-min priming period and was prevented by prior covalent ligation of cell-surface free amino groups by sulpho-N-hydroxy succinimido-biotin; clofilium-mediated inhibition of tucaresol-induced changes in intracellular K+; and selective inhibition of the MAPK pathway [25].
  • Apamin or glybenclamide did not affect the contractile action of galanin, while clofilium attenuated the Emax to the peptide in a concentration-dependent manner, the EC50 of the agent being 9.44 microM (164 nM-541 microM) [26].
  • The effect of clofilium on potassium conductance was studied in excised membrane patches from Chinese hamster ovary cells stably transfected with the Kv1.5/hPCN1 delayed rectifier K+ channel gene [27].

Analytical, diagnostic and therapeutic context of Clofilium


  1. Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization. Carlsson, L., Abrahamsson, C., Drews, L., Duker, G. Circulation (1992) [Pubmed]
  2. Dose-ranging studies of clofilium, an antiarrhythmic quaternary ammonium. Platia, E.V., Reid, P.R. Clin. Pharmacol. Ther. (1984) [Pubmed]
  3. Therapeutic potentiation of the immune system by costimulatory Schiff-base-forming drugs. Rhodes, J., Chen, H., Hall, S.R., Beesley, J.E., Jenkins, D.C., Collins, P., Zheng, B. Nature (1995) [Pubmed]
  4. KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Yang, W.P., Levesque, P.C., Little, W.A., Conder, M.L., Shalaby, F.Y., Blanar, M.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Pharmacological characterisation of a re-entry model for atrial tachycardia in conscious dogs. Wu, K.M., Hunter, T., Proakis, A. Cardiovasc. Res. (1989) [Pubmed]
  6. Antifibrillatory effects of clofilium in the rabbit isolated heart. Friedrichs, G.S., Chi, L., Green, A.L., Lucchesi, B.R. Br. J. Pharmacol. (1994) [Pubmed]
  7. K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in repolarization. Hasumi, H., Matsuda, R., Shimamoto, K., Hata, Y., Kaneko, N. Eur. J. Pharmacol. (2007) [Pubmed]
  8. The effect of bretylium and clofilium on dispersion of refractoriness and vulnerability to ventricular fibrillation in the ischemic feline heart. Kowey, P.R., Friehling, T.D., O'Connor, K.M., Wetstein, L., Kelliher, G.J. Am. Heart J. (1985) [Pubmed]
  9. Prevention of clofilium-induced torsade de pointes by prostaglandin E2 does not involve ATP-dependent K+ channels. Farkas, A., Coker, S.J. Eur. J. Pharmacol. (2003) [Pubmed]
  10. Oral clofilium produces sustained lowering of defibrillation energy requirements in a canine model. Dorian, P., Wang, M., David, I., Feindel, C. Circulation (1991) [Pubmed]
  11. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes. Attali, B., Romey, G., Honoré, E., Schmid-Alliana, A., Mattéi, M.G., Lesage, F., Ricard, P., Barhanin, J., Lazdunski, M. J. Biol. Chem. (1992) [Pubmed]
  12. Contribution of the IsK (MinK) potassium channel subunit to regulatory volume decrease in murine tracheal epithelial cells. Lock, H., Valverde, M.A. J. Biol. Chem. (2000) [Pubmed]
  13. Structural determinants of HERG channel block by clofilium and ibutilide. Perry, M., de Groot, M.J., Helliwell, R., Leishman, D., Tristani-Firouzi, M., Sanguinetti, M.C., Mitcheson, J. Mol. Pharmacol. (2004) [Pubmed]
  14. Functional IsK/KvLQT1 potassium channel in a new corticosteroid-sensitive cell line derived from the inner ear. Teixeira, M., Viengchareun, S., Butlen, D., Ferreira, C., Cluzeaud, F., Blot-Chabaud, M., Lombès, M., Ferrary, E. J. Biol. Chem. (2006) [Pubmed]
  15. Xe991 reveals differences in K(+) channels regulating chloride secretion in murine airway and colonic epithelium. MacVinish, L.J., Guo, Y., Dixon, A.K., Murrell-Lagnado, R.D., Cuthbert, A.W. Mol. Pharmacol. (2001) [Pubmed]
  16. Block of single batrachotoxin-activated Na+ channels by clofilium. Nettleton, J., Castle, N.A., Wang, G.K. Mol. Pharmacol. (1991) [Pubmed]
  17. Molecular basis for the inhibition of 1,4-dihydropyridine calcium channel drugs binding to their receptors by a nonspecific site interaction mechanism. Young, H.S., Skita, V., Mason, R.P., Herbette, L.G. Biophys. J. (1992) [Pubmed]
  18. Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs. Perry, M., Stansfeld, P.J., Leaney, J., Wood, C., de Groot, M.J., Leishman, D., Sutcliffe, M.J., Mitcheson, J.S. Mol. Pharmacol. (2006) [Pubmed]
  19. Voltage-gated K+ currents in freshly isolated myocytes of the pregnant human myometrium. Knock, G.A., Smirnov, S.V., Aaronson, P.I. J. Physiol. (Lond.) (1999) [Pubmed]
  20. Tandem-pore domain potassium channels are functionally expressed in retinal (Müller) glial cells. Skatchkov, S.N., Eaton, M.J., Shuba, Y.M., Kucheryavykh, Y.V., Derst, C., Veh, R.W., Wurm, A., Iandiev, I., Pannicke, T., Bringmann, A., Reichenbach, A. Glia (2006) [Pubmed]
  21. Oxidant stress stimulates anion secretion from the human airway epithelial cell line Calu-3: implications for cystic fibrosis lung disease. Cowley, E.A., Linsdell, P. J. Physiol. (Lond.) (2002) [Pubmed]
  22. Inhibition of hEAG1 and hERG1 potassium channels by clofilium and its tertiary analogue LY97241. Gessner, G., Heinemann, S.H. Br. J. Pharmacol. (2003) [Pubmed]
  23. Molecular determinants for high-affinity block of human EAG potassium channels by antiarrhythmic agents. Gessner, G., Zacharias, M., Bechstedt, S., Schönherr, R., Heinemann, S.H. Mol. Pharmacol. (2004) [Pubmed]
  24. Modulation of calcium-dependent chloride secretion by basolateral SK4-like channels in a human bronchial cell line. Bernard, K., Bogliolo, S., Soriani, O., Ehrenfeld, J. J. Membr. Biol. (2003) [Pubmed]
  25. Schiff base-mediated co-stimulation primes the T-cell-receptor-dependent calcium signalling pathway in CD4 T cells. Hall, S.R., Rhodes, J. Immunology (2001) [Pubmed]
  26. Contractile effects of porcine galanin(1-29)-NH2 on the rat isolated gastric fundus: mediation by potassium ions. Korolkiewicz, R., Takeuchi, K., Sliwinski, W., Konstanski, Z., Rekowski, P., Szyk, A. Pharmacol. Res. (1997) [Pubmed]
  27. Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel. Malayev, A.A., Nelson, D.J., Philipson, L.H. Mol. Pharmacol. (1995) [Pubmed]
  28. Effects of clofilium on ischemic subendocardial Purkinje fibers 1 day postinfarction. Gough, W.B., Hu, D., el-Sherif, N. J. Am. Coll. Cardiol. (1988) [Pubmed]
  29. Block of gating currents related to K+ channels as a mechanism of action of clofilium and d-sotalol in isolated guinea-pig ventricular heart cells. Malécot, C.O., Argibay, J.A. Br. J. Pharmacol. (1999) [Pubmed]
  30. Nasal drug delivery system of a quaternary ammonium compound: clofilium tosylate. Su, K.S., Campanale, K.M., Gries, C.L. Journal of pharmaceutical sciences. (1984) [Pubmed]
  31. Antiarrhythmic and electrophysiologic actions of clofilium in experimental canine models. Kopia, G.A., Eller, B.T., Patterson, E., Shea, M.J., Lucchesi, B.R. Eur. J. Pharmacol. (1985) [Pubmed]
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