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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.EJ

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+Show Affiliations

Aventis Pharmaceuticals, Inc., Mail Code: EM-A1A, Route 202-206, P.O. Box 6800, Bridgewater, NJ 08807-0800, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

12176106

Citation

Kongsamut, Sathapana, et al. "A Comparison of the Receptor Binding and HERG Channel Affinities for a Series of Antipsychotic Drugs." European Journal of Pharmacology, vol. 450, no. 1, 2002, pp. 37-41.
Kongsamut S, Kang J, Chen XL, et al. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. Eur J Pharmacol. 2002;450(1):37-41.
Kongsamut, S., Kang, J., Chen, X. L., Roehr, J., & Rampe, D. (2002). A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. European Journal of Pharmacology, 450(1), 37-41.
Kongsamut S, et al. 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 PMID: 12176106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. AU - Kongsamut,Sathapana, AU - Kang,Jiesheng, AU - Chen,Xiao-Liang, AU - Roehr,Joachim, AU - Rampe,David, PY - 2002/8/15/pubmed PY - 2003/4/2/medline PY - 2002/8/15/entrez SP - 37 EP - 41 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 450 IS - 1 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/12176106/A_comparison_of_the_receptor_binding_and_HERG_channel_affinities_for_a_series_of_antipsychotic_drugs_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014299902020745 DB - PRIME DP - Unbound Medicine ER -