Pharmaceutical Research

, Volume 23, Issue 6, pp 1133–1143

Effects of Antipsychotic Drugs on Ito, INa, Isus, IK1, and hERG: QT Prolongation, Structure Activity Relationship, and Network Analysis

  • William J. CrumbJr.
  • Sean Ekins
  • R. Dustan Sarazan
  • James H. Wikel
  • Steven A. Wrighton
  • Christopher Carlson
  • Charles M. BeasleyJr.
Feature Article


To evaluate in vitro and computationally model the effects of selected antipsychotic drugs on several ionic currents that contribute to changes in the action potential in cardiac tissue.


Fourteen antipsychotic drugs or metabolites were examined to determine whether QT interval prolongation could be accounted for by an effect on one or more myocardial ion channels [Ito, INa, Isus, IK1, and human ether-a-go-go related gene (hERG)]. Using the patch clamp technique, drug effects on these human cardiac currents were tested.


All molecules had little inhibitory effect on ion channels (blocking at concentrations >5 μM) other than hERG. A significant correlation was observed between the estimated hERG blockade and the increase in corrected QT for five of the antipsychotics. Molecular modeling identified hydrophobic features related to the interaction with hERG and correctly rank-ordered the test set molecules olanzapine and its metabolites. A network analysis of ligand and protein interactions around hERG using MetaCore™ (GeneGo Inc., St. Joseph, MI, USA) was used to visualize antipsychotics with affinity for this channel and their interactions with other proteins in this database.


The antipsychotics do not inhibit the ion channels Ito, INa, Isus, IK1 to any appreciable extent; however, blockade of hERG is a likely mechanism for the prolongation of the QT interval.

Key Words

antipsychotics cardiac ion channels hERG QT 



human ether-a-go-go related gene


the inwardly rectifying potassium current


sodium current


sustained potassium current


transient outward potassium current


  1. 1.
    Thomas, S. H. 1994Drugs, QT interval abnormalities and ventricular arrhythmiasAdverse Drug React. Toxicol. Rev.1377102PubMedGoogle Scholar
  2. 2.
    Barry, D. M., Xu, H., Schuessler, R. B., Nerbonne, J. M. 1998Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunitCirc. Res.83560567PubMedGoogle Scholar
  3. 3.
    Trudeau, M. C., Warmke, J. W., Ganetzky, B., Robertson, G. A. 1995HERG, a human inward rectifier in the voltage-gated potassium channel familyScience2699295PubMedGoogle Scholar
  4. 4.
    Warmke, J. W., Ganetzky, B. 1994A family of potassium channel genes related to eag in Drosophila and mammalsProc. Natl. Acad. Sci. USA9134383442PubMedCrossRefGoogle Scholar
  5. 5.
    Sanguinetti, M. C., Jiang, C., Curran, M. E., Keating, M. T. 1995A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channelCell81299307PubMedCrossRefGoogle Scholar
  6. 6.
    Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., Keating, M. T. 1995A molecular basis for the cardiac arrhythmia: HERG mutations cause long QT syndromeCell80795803PubMedCrossRefGoogle Scholar
  7. 7.
    Suessbrich, H., Schonherr, R., Heinemann, S. H., Attali, B., Lang, F., Busch, A. E. 1997The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytesBr. J. Pharmacol.120968974PubMedGoogle Scholar
  8. 8.
    Jeron, A., Mitchell, G. F., Zhou, J., Murata, M., London, B., Buckett, P., Wiviott, S. D., Koren, G. 2000Inducible polymorphic ventricular tachyarrhythmias in a transgenic mouse model with a long Q–T phenotypeAm. J. Physiol. Heart Circ. Physiol.278H1891H1898PubMedGoogle Scholar
  9. 9.
    Welchand, R., Chue, P. 2000Antipsychotic agents and QT changesJ. Psychiatry Neurosci.25154160Google Scholar
  10. 10.
    Mehta, D., Mehta, S., Petit, J., Shriner, W. 1979Cardiac arrhythmia and haloperidolAm. J. Psychiatr.13614681469PubMedGoogle Scholar
  11. 11.
    Ekins, S., Crumb, W. J., Sarazan, R. D., Wikel, J. H., Wrighton, S. A. 2002Three-dimensional quantitative structure–activity relationship for inhibition of human ether-a-go-go-related gene potassium channelJ. Pharmacol. Exp. Ther.301427434PubMedCrossRefGoogle Scholar
  12. 12.
    Crumb, W. J.,Jr., Pigott, J. D., Clarkson, C. W. 1995Comparison of Ito in young and adult human atrial myocytes: evidence for developmental changesAm. J. Physiol.268H1335H1342PubMedGoogle Scholar
  13. 13.
    Hamill, O. P., Marty, A., Neher, E., Sakmann, B., Sigworth, F. J. 1981Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patchesPflugers Arch.39185100PubMedCrossRefGoogle Scholar
  14. 14.
    Ekins, S., Bugrim, A., Nikolsky, Y., Nikolskaya, T. 2005

    Systems biology: applications in drug discovery

    Gad, S. C. eds. Drug Discovery HandbookWileyNew York123183
    Google Scholar
  15. 15.
    Ekins, S., Kirillov, E., Rakhmatulin, E. A., Nikolskaya, T. 2005A Novel Method for Visualizing Nuclear Hormone Receptor Networks Relevant to Drug MetabolismDrug Metab. Dispos.33474481PubMedCrossRefGoogle Scholar
  16. 16.
    Harrigan, E. P., Miceli, J. J., Anziano, R., Watsky, E., Reeves, K. R., Cutler, N. R., Sramek, J., Shiovitz, T., Middle, M. 2004A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibitionJ. Clin. Psychopharmacol.246269PubMedCrossRefGoogle Scholar
  17. 17.
    Pfizer briefing document for Zeldox Capsules (Ziprasidone HCl). July 19, 2000.Google Scholar
  18. 18.
    Titier, K., Canal, M., Deridet, E., Abouelfath, A., Gromb, S., Molimard, M., Moore, N. 2004Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practiceToxicol. Appl. Pharmacol.1995260PubMedCrossRefGoogle Scholar
  19. 19.
    Malik, M. 2001Problems of heart rate correction in assessment of drug-induced QT interval prolongationJ. Cardiovasc. Electrophysiol.12411420PubMedCrossRefGoogle Scholar
  20. 20.
    Malik, M., Camm, A. J. 2001Evaluation of drug-induced QT interval prolongation: implications for drug approval and labellingDrug Safety24323351PubMedCrossRefGoogle Scholar
  21. 21.
    Shah, R. R. 2002The significance of QT interval in drug developmentBr. J. Clin. Pharmacol.54188202PubMedCrossRefGoogle Scholar
  22. 22.
    Witchel, H. J., Hancox, J. C., Nutt, D. J. 2003Psychotropic drugs, cardiac arrhythmia, and sudden deathJ. Clin. Psychopharmacol.235877PubMedCrossRefGoogle Scholar
  23. 23.
    Webster, R., Leishman, D., Walker, D. 2002Towards a drug concentration effect relationship for QT prolongation and torsades de pointesCurr. Opin. Drug Discov. Dev.5116126Google Scholar
  24. 24.
    Crumband, W., Cavero, I. 1999QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug developmentPSST2270280Google Scholar
  25. 25.
    Zhang, S., Zhou, Z., Gong, Q., Makielski, J. C., January, C. T. 1999Mechanism of block and identification of the verapamil binding domain to HERG potassium channelsCirc. Res.84989998PubMedGoogle Scholar
  26. 26.
    Kang, J., Chen, X. L., Wang, H., Ji, J., Reynolds, W., Lim, S., Hendrix, J., Rampe, D. 2004Cardiac ion channel effects of tolterodineJ. Pharmacol. Exp. Ther.308935940PubMedCrossRefGoogle Scholar
  27. 27.
    Thomsen, M. B., Volders, P. G., Stengl, M., Spatjens, R. L., Beekman, J. D., Bischoff, U., Kall, M. A., Frederiksen, K., Matz, J., Vos, M. A. 2003Electrophysiological safety of sertindole in dogs with normal and remodeled heartsJ. Pharmacol. Exp. Ther.307776784PubMedCrossRefGoogle Scholar
  28. 28.
    Belpaire, F. M., Vanderheeren, F. A., Bogaert, M. G. 1975Binding of thioridazine and some of its metabolites to human serum protein and human albuminArzneim. Forsch.2519691971Google Scholar
  29. 29.
    Niemann, J. T., Stapczynski, J. S., Rothstein, R. J., Laks, M. M. 1981Cardiac conduction and rhythm disturbances following suicidal ingestion of mesoridazineAnn. Emerg. Med.10585588PubMedCrossRefGoogle Scholar
  30. 30.
    Fayer, S. A. 1986Torsades de pointes ventricular tachyarrhythmia associated with haloperidolJ. Clin. Psychopharmacol.6375376PubMedGoogle Scholar
  31. 31.
    Paakkari, I. 2002Cardiotoxicity of new antihistamines and cisaprideToxicol. Lett.127279284PubMedCrossRefGoogle Scholar
  32. 32.
    Nasrallah, H. A. 1978Factors influencing phenothiazine-induced ECG changesAm. J. Psychiatr.135118119PubMedGoogle Scholar
  33. 33.
    Aunsholt, N. A. 1989Prolonged Q–T interval and hypokalemia caused by haloperidolActa Psychiatr. Scand.79411412PubMedGoogle Scholar
  34. 34.
    Siddiqui, M. N., Zafar, H., Alvi, R., Ahmed, M. 1998Hypomagnesaemia in postoperative patients: an important contributing factor in postoperative mortalityInt. J. Clin. Pract.52265267PubMedGoogle Scholar
  35. 35.
    Ekins, S., Swaan, P. W. 2004Development of computational models for enzymes, transporters, channels and receptors relevant to ADME/TOXRev. Comp. Chem.20333415CrossRefGoogle Scholar
  36. 36.
    Mitcheson, J. S., Chen, J., Lin, M., Culberson, C., Sanguinetti, M. C. 2000A structural basis for drug-induced long QT syndromeProc. Natl. Acad. Sci. U. S. A.971232912333PubMedCrossRefGoogle Scholar
  37. 37.
    Ekins, S. 2004Predicting undesirable drug interactions with promiscuous proteins in silicoDrug Discov. Today9276285PubMedCrossRefGoogle Scholar
  38. 38.
    Li, H., Sutter, J., Hoffman, R. 2000

    HypoGen: an automated system for generating 3D predictive pharmacophore models

    Guner, O. F. eds. Pharmacophore Perception, Development, and Use in Drug DesignIULSan Diego173189
    Google Scholar
  39. 39.
    Mitcheson, J. S. 2003Drug binding to HERG channels: evidence for a ‘non-aromatic’ binding site for fluvoxamineBr. J. Pharmacol.139883884PubMedCrossRefGoogle Scholar
  40. 40.
    Huys, I., Xu, C. Q., Wang, C. Z., Vacher, H., Martin-Eauclaire, M. F., Chi, C. W., Tytgat, J. 2004BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currentsBiochem. J.378745752PubMedCrossRefGoogle Scholar
  41. 41.
    Korolkova, Y. V., Bocharov, E. V., Angelo, K., Maslennikov, I. V., Grinenko, O. V., Lipkin, A. V., Nosyreva, E. D., Pluzhnikov, K. A., Olesen, S. P., Areseniev, A. S., Grishin, E. V. 2002New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1J. Biol. Chem.2774310443109PubMedCrossRefGoogle Scholar
  42. 42.
    Torres, A. M., Bansal, P., Alewood, P. F., Bursill, J. A., Kuchel, P. W., Vandenberg, J. I. 2003Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxinFEBS Lett.539138142PubMedCrossRefGoogle Scholar
  43. 43.
    Ekins, S. 2004Predicting undesirable drug interactions with promiscuous proteins in silicoDrug Discov. Today9276285PubMedCrossRefGoogle Scholar
  44. 44.
    Luca, A., Talon, S., Bellis, M., Desaphy, J. F., Lentini, G., Corbo, F., Scilimati, A., Franchini, C., Tortorella, V., Camerino, D. C. 2003Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compoundsMol. Pharmacol.64932945PubMedCrossRefGoogle Scholar
  45. 45.
    Goodman, L. S., Limbard, L. E., Molinoff, P. B., Ruddon, R. W., Gilman, A. G. 2003Goodman & Gilman’s the Pharmacological Basis of TherapeuticsMcGraw-HillNew YorkGoogle Scholar
  46. 46.
    Physicians’ Desk Reference (PDR), Medical Economics, Thompson Healthcare, Montvale, NJ, 2004.Google Scholar
  47. 47.
    Dinovo, E. C., Pollak, H., Gottschalk, L. A. 1984Partitioning of thioridazine and mesoridazine in human blood fractionsMethods Find. Exp. Clin. Pharmacol.6143146PubMedGoogle Scholar
  48. 48.
    Nyberg, G., Axelsson, R., Martensson, E. 1978Binding of thioridazine and thioridazine metabolites to serum proteins in psychiatric patientsEur. J. Clin. Pharmacol.14341350PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • William J. CrumbJr.
    • 1
  • Sean Ekins
    • 2
    • 4
  • R. Dustan Sarazan
    • 2
    • 5
  • James H. Wikel
    • 2
    • 6
  • Steven A. Wrighton
    • 2
  • Christopher Carlson
    • 2
  • Charles M. BeasleyJr.
    • 2
    • 3
  1. 1.Department of Pediatrics (Cardiology)Tulane University School of MedicineNew OrleansUSA
  2. 2.Lilly Research Laboratories, Elli Lilly and Co.IndianapolisUSA
  3. 3.Lilly Corporate CenterIndianapolisUSA
  4. 4.GeneGo, Inc., 500 Renaissance Drive, Suite 106, St. Joseph, Michigan 49085, USAGeneGo Inc.JenkintownUSA
  5. 5.Covance Laboratories Inc.MadisonUSA
  6. 6.Coalesix Inc.CambridgeUSA

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