Effects of antipsychotic drugs on I(to), I (Na), I (sus), I (K1), and hERG: QT prolongation, structure activity relationship, and network analysis.
OBJECTIVE
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 [I(to), I(Na), I(sus), I(K1), 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 microM) 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.


CONCLUSIONS
The antipsychotics do not inhibit the ion channels I(to), I(Na), I(sus), I(K1) to any appreciable extent; however, blockade of hERG is a likely mechanism for the prolongation of the QT interval.
Crumb
William J
WJ
Department of Pediatrics (Cardiology), Tulane University School of Medicine, New Orleans, Lousiana, USA.
Ekins
Sean
S
Sarazan
R Dustan
RD
Wikel
James H
JH
Wrighton
Steven A
SA
Carlson
Christopher
C
Beasley
Charles M
CM
D000200:Action Potentials; D000368:Aged; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology / Q000633:toxicity; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D016571:Neural Networks, Computer; D000077152:Olanzapine; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013881:Thioridazine / Q000494:pharmacology / Q000633:toxicity; D014162:Transfection
D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D007211:Indoles; D007473:Ion Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D015222:Sodium Channels; D001569:Benzodiazepines; C066304:sertindole; D013881:Thioridazine; D000077152:Olanzapine