Effects of Antipsychotic Drugs on Ito, INa, Isus, IK1, and hERG: QT Prolongation, Structure Activity Relationship, and Network Analysis
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- Crumb, W.J., Ekins, S., Sarazan, R.D. et al. Pharm Res (2006) 23: 1133. doi:10.1007/s11095-006-0070-7
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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 Wordsantipsychotics cardiac ion channels hERG QT
human ether-a-go-go related gene
the inwardly rectifying potassium current
sustained potassium current
transient outward potassium current