Feature Article

Pharmaceutical Research

, Volume 23, Issue 6, pp 1133-1143

First online:

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

  • William J. CrumbJr.Affiliated withDepartment of Pediatrics (Cardiology), Tulane University School of Medicine
  • , Sean EkinsAffiliated withLilly Research Laboratories, Elli Lilly and Co.GeneGo, Inc., 500 Renaissance Drive, Suite 106, St. Joseph, Michigan 49085, USA, GeneGo Inc. Email author 
  • , R. Dustan SarazanAffiliated withLilly Research Laboratories, Elli Lilly and Co.Covance Laboratories Inc.
  • , James H. WikelAffiliated withLilly Research Laboratories, Elli Lilly and Co.Coalesix Inc.
  • , Steven A. WrightonAffiliated withLilly Research Laboratories, Elli Lilly and Co.
  • , Christopher CarlsonAffiliated withLilly Research Laboratories, Elli Lilly and Co.
  • , Charles M. BeasleyJr.Affiliated withLilly Research Laboratories, Elli Lilly and Co.Lilly Corporate Center

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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

antipsychotics cardiac ion channels hERG QT