title: Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues.
abstract: OBJECTIVE
  Amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran, B2-O-CH(2)CH(2)-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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Compared with amiodarone, which displayed only a weak cytotoxicity, the mono- and bis-desethylated metabolites, the further degraded alcohol (B2-O-CH(2)-CH(2)-OH), the corresponding acid (B2-O-CH(2)-COOH) and, finally, the newly synthesized B2-O-CH(2)-CH(2)-N-pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2-O-CH(2)-CH(2)-N-diisopropyl and the B2-O-CH(2)-CH(2)-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-CH(2)-CH(2)-N-piperidine and B2-O-CH(2)-CH(2)-N-pyrrolidine revealed a higher affinity towards hERG channels than amiodarone.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical Pharmacology & Toxicology, Department of Research, University Hospital Basel, Basel, Switzerland.
authors.forename: K M
authors.initials: KM
authors.lastname: Waldhauser
authors.forename: K
authors.initials: K
authors.lastname: Brecht
authors.forename: S
authors.initials: S
authors.lastname: Hebeisen
authors.forename: H R
authors.initials: HR
authors.lastname: Ha
authors.forename: D
authors.initials: D
authors.lastname: Konrad
authors.forename: D
authors.initials: D
authors.lastname: Bur
authors.forename: S
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D000638:Amiodarone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D000638:Amiodarone