title: A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs.
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.
authors.affiliation: Aventis Pharmaceuticals, Inc., Mail Code: EM-A1A, Route 202-206, P.O. Box 6800, Bridgewater, NJ 08807-0800, USA.
authors.forename: Sathapana
authors.initials: S
authors.lastname: Kongsamut
authors.forename: Jiesheng
authors.initials: J
authors.lastname: Kang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Chen
authors.forename: Joachim
authors.initials: J
authors.lastname: Roehr
authors.forename: David
authors.initials: D
authors.lastname: Rampe
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D027682:Cation Transport Proteins; D002460:Cell Line; D002986:Clinical Trials as Topic; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
chemical_list: D014150:Antipsychotic Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG