A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs.

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Kongsamut S, Kang J, Chen XL, Roehr J, Rampe D

A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs.

Eur J Pharmacol. 2002 Aug 16;450(1):37-41.

PubMed ID
12176106 [ View in PubMed
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Abstract

Many antipsychotic drugs produce QT interval prolongation on the electrocardiogram (ECG). Blockade of the human cardiac K(+) channel known as human ether-a-go-go-related gene (HERG) often underlies such clinical findings. In fact, HERG channel inhibition is now commonly used as a screen to predict the ability of a drug to prolong QT interval. However, the exact relationship between HERG channel blockade, target receptor binding affinity and clinical QT prolongation is not known. Using patch-clamp electrophysiology, we examined a series of seven antipsychotic drugs for their ability to block HERG, and determined their IC(50) values. We then compared these results to their binding affinities (K(i) values) for the dopamine D(2) receptor, the 5-HT(2A) receptor and, where available, to clinical QT prolongation data. We found that sertindole, pimozide and thioridazine displayed little (<10-fold) or no selectivity for dopamine D(2) or 5-HT(2A) receptors relative to their HERG channel affinities. This lack of selectivity likely underlies the significant QT interval prolongation observed with administration of these drugs. Of the other drugs tested (ziprasidone, quetiapine, risperidone and olanzapine), olanzapine displayed the greatest selectivity for dopamine D(2) and 5-HT(2A) receptor binding (100-1000-fold) compared to its HERG channel IC(50). We also compared these HERG channel IC(50) values to QT interval prolongation and plasma drug levels obtained in a recent clinical study. We found that the ratio of total plasma drug concentration to HERG IC(50) value was indicative of the degree of QT prolongation observed. Target receptor affinity and expected clinical plasma levels are important parameters to consider for the interpretation of HERG channel data.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Quetiapine5-hydroxytryptamine receptor 2AKi (nM)427N/AN/ADetails
Sertindole5-hydroxytryptamine receptor 2AKi (nM)0.6N/AN/ADetails
Thioridazine5-hydroxytryptamine receptor 2AKi (nM)42.3N/AN/ADetails
Ziprasidone5-hydroxytryptamine receptor 2AKi (nM)0.5N/AN/ADetails