Fluorescently labeled analogues of dofetilide as high-affinity fluorescence polarization ligands for the human ether-a-go-go-related gene (hERG) channel.
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Singleton DH, Boyd H, Steidl-Nichols JV, Deacon M, Groot MJ, Price D, Nettleton DO, Wallace NK, Troutman MD, Williams C, Boyd JG
Fluorescently labeled analogues of dofetilide as high-affinity fluorescence polarization ligands for the human ether-a-go-go-related gene (hERG) channel.
J Med Chem. 2007 Jun 28;50(13):2931-41. Epub 2007 May 31.
- PubMed ID
- 17536794 [ View in PubMed]
- Abstract
Novel fluorescent derivatives of dofetilide (1) have been synthesized. Analogues that feature a fluorescent probe attached through an aliphatic spacer to the central tertiary nitrogen of 1 have high affinity for the hERG channel, and affinity is dependent on both linker length and pendent dye. These variables have been optimized to generate Cy3B derivative 10e, which has hERG channel affinity equivalent to that of dofetilide. When bound to cell membranes expressing the hERG channel, 10e shows a robust increase in fluorescence polarization (FP) signal. In a FP binding assay using 10e as tracer ligand, Ki values for several known hERG channel blockers were measured and excellent agreement with the literature Ki values was observed over an affinity range of 2 nM to 3 muM. 10e blocks hERG channel current in electrophysiological patch clamp experiments, and computational docking experiments predict that the dofetilide core of 10e binds hERG channel in a conformation similar to that previously predicted for 1. These analogues enable high-throughput hERG channel binding assays that are rapid, economical, and predictive of test compounds' potential for prolonged QT liabilities.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Astemizole Potassium voltage-gated channel subfamily H member 2 Ki (nM) 2.9 N/A N/A Details Astemizole Potassium voltage-gated channel subfamily H member 2 Ki (nM) 12.8 N/A N/A Details Bepridil Potassium voltage-gated channel subfamily H member 2 Ki (nM) 291 N/A N/A Details Bepridil Potassium voltage-gated channel subfamily H member 2 Ki (nM) 184 N/A N/A Details Dofetilide Potassium voltage-gated channel subfamily H member 2 Ki (nM) 6.4 N/A N/A Details Dofetilide Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 9.2 N/A N/A Details Dofetilide Potassium voltage-gated channel subfamily H member 2 Ki (nM) 7.7 N/A N/A Details