Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel

Zhiyi Yu, Jacobus P.D. Van Veldhoven, Ingrid M.E. 'T Hart, Adrian H. Kopf, Laura H. Heitman, Adriaan P. Ijzerman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [3H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.

Original languageEnglish
Pages (from-to)50-59
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume106
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

Keywords

  • Antiarrhythmia
  • K11.1 blockers
  • K11.1(hERG) channel
  • Negative allosteric modulator
  • Radioligand binding assay

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