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Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues

Waldhauser, Katri M. and Brecht, Karin and Hebeisen, S. and Ha, H. R. and Konrad, D. and Bur, Daniel and Krähenbühl, Stephan. (2008) Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues. British journal of pharmacology, 155 (4). pp. 585-595.

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Official URL: http://edoc.unibas.ch/dok/A6004840

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Abstract

Amiodarone (2‐n‐butyl‐3‐[3,5 diiodo‐4‐diethylaminoethoxybenzoyl]‐benzofuran, B2‐O‐CH2CH2‐N‐diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life‐threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether‐a‐go‐go‐related protein (hERG) channel inhibition but with reduced cytotoxicity. We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological and in silico methods. Compared with amiodarone, which displayed only a weak cytotoxicity, the mono‐ and bis‐desethylated metabolites, the further degraded alcohol (B2‐O‐CH2‐CH2‐OH), the corresponding acid (B2‐O‐CH2‐COOH) and, finally, the newly synthesized B2‐O‐CH2‐CH2‐N‐pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2‐O‐CH2‐CH2‐N‐diisopropyl and the B2‐O‐CH2‐CH2‐N‐piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological and in silico investigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2‐O‐CH2‐CH2‐N‐piperidine and B2‐O‐CH2‐CH2‐N‐pyrrolidine revealed a higher affinity towards hERG channels than amiodarone. Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
05 Faculty of Science
05 Faculty of Science > Departement Pharmazeutische Wissenschaften
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Brecht Brüngger, Karin and Krähenbühl, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
ISSN:0007-1188
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:19 Aug 2020 10:27
Deposited On:25 Apr 2014 08:01

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