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

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 IC50 values. We then compared these results to their binding affinities (Ki values) for the dopamine D2 receptor, the 5-HT2A receptor and, where available, to clinical QT prolongation data. We found that sertindole, pimozide and thioridazine displayed little (