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Interactions at the human ether a go‐go (hERG) potassium channel investigated through multiple radioligands
Author(s) -
Au Eugene,
Vu Amanda,
Ly Justin Q,
Misner Dinah L,
Kondru Rama K,
Martin Renee S
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1112-b
Subject(s) - herg , astemizole , dofetilide , chemistry , pharmacology , radioligand , potassium channel , haloperidol , stereochemistry , biophysics , binding site , biochemistry , medicine , dopamine , biology , qt interval
OBJECTIVE AND METHODS The objective of this study was to explore potentially different modes of binding to the hERG channel through competition binding with three different radioligands: dofetilide, haloperidol, and astemizole. Affinities of unlabelled ligands were determined in cell membranes derived from Chinese Hamster Ovary cells recombinantly expressing the hERG channel. RESULTS Binding affinities of various well known hERG ligands determined by the displacement of [ 3 H]‐dofetilide and [ 3 H]‐astemizole agreed well, but differed from the affinity values determined by the displacement of [ 3 H]‐haloperidol. In these studies, the radioligand concentrations used were 4, 1, and 0.4 times the K d for dofetilide, haloperidol, and astemizole, respectively.The observed pIC 50 values suggest that dofetilide and astemizole bind to similar domains of the hERG channel, and different to that of haloperidol. These results have been considered in the context of functional electrophysiology data and channel homology modeling. CONCLUSIONS Multi‐radioligand screening may enable higher throughput preclinical assessment of hERG liability and its implications with respect to drug safety. Further, such screening provides a new way to assess the nature of ligand interaction at the hERG channel.