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

DOI: 10.1007/s11095-006-0070-7

Cite this article as:
Crumb, W.J., Ekins, S., Sarazan, R.D. et al. Pharm Res (2006) 23: 1133. doi:10.1007/s11095-006-0070-7

Purpose

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.

Methods

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.

Results

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.

Conclusion

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

antipsychoticscardiac ion channelshERGQT

Abbreviations

hERG

human ether-a-go-go related gene

IK1

the inwardly rectifying potassium current

INa

sodium current

Isus

sustained potassium current

Ito

transient outward potassium current

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