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Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Nov; 368(5):404-14.NS

Abstract

Budipine is a non-dopaminergic antiparkinsonian drug causing acquired forms of Long QT syndrome (aLQTS). As a consequence, the manufacturer has restricted the use of budipine in patients who exhibit additional risk factors for the development of "Torsades-de-Pointes" tachycardias (TdP). The molecular basis of this serious side effect has not been elucidated yet. Human ether-a-go-go related gene (HERG) channel block being the main cause of drug induced QT prolongation, we investigated the effect of budipine on the rapid component of the delayed-rectifier potassium current (I(K(r))) in guinea pig cardiomyocytes and on HERG potassium channels heterologously expressed in Xenopus oocytes. In guinea pig cardiomyocytes, budipine (10 microM) inhibited I(K(r)) by 86% but was without any effect on calcium currents. In Xenopus oocytes, HERG potassium channels were blocked by budipine with an IC(50) of 10.2 microM. Onset of block was fast and block was only slowly and incompletely reversible upon washout. Budipine blocked HERG channels in the open and inactivated state, but not in the closed states. The half-maximal activation voltage was slightly shifted towards more negative potentials. Steady-state inactivation of HERG was also influenced by budipine. Budipine block was neither voltage- nor frequency-dependent. In HERG channel mutants Y652A and F656A, drug affinity was reduced dramatically. Therefore, these two aromatic residues in the channel pore are likely to form a main part of the binding site for budipine. In summary, this is the first study that provides a molecular basis for the budipine-associated aLQTS observed in clinical practice. Furthermore, these findings underline the importance of the aromatic residues Y652 and F656 in the binding of lipophilic drugs to HERG channels.

Authors+Show Affiliations

3rd Department of Internal Medicine (Cardiology), University of Heidelberg Medical School, Bergheimerstrasse 58, 69115, Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14557918

Citation

Scholz, Eberhard P., et al. "Drug Binding to Aromatic Residues in the HERG Channel Pore Cavity as Possible Explanation for Acquired Long QT Syndrome By Antiparkinsonian Drug Budipine." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 368, no. 5, 2003, pp. 404-14.
Scholz EP, Zitron E, Kiesecker C, et al. Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine. Naunyn Schmiedebergs Arch Pharmacol. 2003;368(5):404-14.
Scholz, E. P., Zitron, E., Kiesecker, C., Lueck, S., Kathöfer, S., Thomas, D., Weretka, S., Peth, S., Kreye, V. A., Schoels, W., Katus, H. A., Kiehn, J., & Karle, C. A. (2003). Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine. Naunyn-Schmiedeberg's Archives of Pharmacology, 368(5), 404-14.
Scholz EP, et al. Drug Binding to Aromatic Residues in the HERG Channel Pore Cavity as Possible Explanation for Acquired Long QT Syndrome By Antiparkinsonian Drug Budipine. Naunyn Schmiedebergs Arch Pharmacol. 2003;368(5):404-14. PubMed PMID: 14557918.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine. AU - Scholz,Eberhard P, AU - Zitron,Edgar, AU - Kiesecker,Claudia, AU - Lueck,Sonja, AU - Kathöfer,Sven, AU - Thomas,Dierk, AU - Weretka,Slawomir, AU - Peth,Simon, AU - Kreye,Volker A W, AU - Schoels,Wolfgang, AU - Katus,Hugo A, AU - Kiehn,Johann, AU - Karle,Christoph A, Y1 - 2003/10/14/ PY - 2003/06/17/received PY - 2003/08/20/accepted PY - 2003/10/15/pubmed PY - 2004/2/11/medline PY - 2003/10/15/entrez SP - 404 EP - 14 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch Pharmacol VL - 368 IS - 5 N2 - Budipine is a non-dopaminergic antiparkinsonian drug causing acquired forms of Long QT syndrome (aLQTS). As a consequence, the manufacturer has restricted the use of budipine in patients who exhibit additional risk factors for the development of "Torsades-de-Pointes" tachycardias (TdP). The molecular basis of this serious side effect has not been elucidated yet. Human ether-a-go-go related gene (HERG) channel block being the main cause of drug induced QT prolongation, we investigated the effect of budipine on the rapid component of the delayed-rectifier potassium current (I(K(r))) in guinea pig cardiomyocytes and on HERG potassium channels heterologously expressed in Xenopus oocytes. In guinea pig cardiomyocytes, budipine (10 microM) inhibited I(K(r)) by 86% but was without any effect on calcium currents. In Xenopus oocytes, HERG potassium channels were blocked by budipine with an IC(50) of 10.2 microM. Onset of block was fast and block was only slowly and incompletely reversible upon washout. Budipine blocked HERG channels in the open and inactivated state, but not in the closed states. The half-maximal activation voltage was slightly shifted towards more negative potentials. Steady-state inactivation of HERG was also influenced by budipine. Budipine block was neither voltage- nor frequency-dependent. In HERG channel mutants Y652A and F656A, drug affinity was reduced dramatically. Therefore, these two aromatic residues in the channel pore are likely to form a main part of the binding site for budipine. In summary, this is the first study that provides a molecular basis for the budipine-associated aLQTS observed in clinical practice. Furthermore, these findings underline the importance of the aromatic residues Y652 and F656 in the binding of lipophilic drugs to HERG channels. SN - 0028-1298 UR - https://www.unboundmedicine.com/medline/citation/14557918/Drug_binding_to_aromatic_residues_in_the_HERG_channel_pore_cavity_as_possible_explanation_for_acquired_Long_QT_syndrome_by_antiparkinsonian_drug_budipine_ L2 - https://dx.doi.org/10.1007/s00210-003-0805-5 DB - PRIME DP - Unbound Medicine ER -