Allosteric modulators of the hERG K(+) channel: radioligand binding assays reveal allosteric characteristics of dofetilide analogs

Toxicol Appl Pharmacol. 2014 Jan 1;274(1):78-86. doi: 10.1016/j.taap.2013.10.024. Epub 2013 Nov 5.


Drugs that block the cardiac K(+) channel encoded by the human ether-à-go-go gene (hERG) have been associated with QT interval prolongation leading to proarrhythmia, and in some cases, sudden cardiac death. Because of special structural features of the hERG K(+) channel, it has become a promiscuous target that interacts with pharmaceuticals of widely varying chemical structures and a reason for concern in the pharmaceutical industry. The structural diversity suggests that multiple binding sites are available on the channel with possible allosteric interactions between them. In the present study, three reference compounds and nine compounds of a previously disclosed series were evaluated for their allosteric effects on the binding of [(3)H]astemizole and [(3)H]dofetilide to the hERG K(+) channel. LUF6200 was identified as an allosteric inhibitor in dissociation assays with both radioligands, yielding similar EC50 values in the low micromolar range. However, potassium ions increased the binding of the two radioligands in a concentration-dependent manner, and their EC50 values were not significantly different, indicating that potassium ions behaved as allosteric enhancers. Furthermore, addition of potassium ions resulted in a concentration-dependent leftward shift of the LUF6200 response curve, suggesting positive cooperativity and distinct allosteric sites for them. In conclusion, our investigations provide evidence for allosteric modulation of the hERG K(+) channel, which is discussed in the light of findings on other ion channels.

Keywords: Allosteric modulator; LUF6200; Potassium ions; [(3)H]astemizole; [(3)H]dofetilide; hERG K(+) channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • HEK293 Cells
  • Humans
  • Phenethylamines / chemistry
  • Phenethylamines / metabolism*
  • Phenethylamines / pharmacology
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / metabolism*
  • Potassium Channel Blockers / pharmacology
  • Protein Binding / physiology
  • Radioligand Assay / methods*
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism*
  • Sulfonamides / pharmacology


  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Phenethylamines
  • Potassium Channel Blockers
  • Sulfonamides
  • dofetilide