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

doi:10.1016/j.ejmech.2015.10.032

Synthesis and biological evaluation of negative allosteric modulators of the K_v11.1(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 journal › Article › Academic › peer-review

Abstract

We synthesized and evaluated a series of compounds for their allosteric modulation at the K_v11.1 (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 K_v11.1 blockers.

Original language	English
Pages (from-to)	50-59
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	106
DOIs	https://doi.org/10.1016/j.ejmech.2015.10.032
Publication status	Published - 1 Dec 2015
Externally published	Yes

Bibliographical note

Funding Information:
Zhiyi Yu is supported by a scholarship from the Chinese Scholarship Council . The authors thank Dr. Julien Louvel for carefully checking and discussing the chemistry paragraphs in the main text and the SI.

Publisher Copyright:
© 2015 Elsevier Masson SAS. All rights reserved.

Funding

Zhiyi Yu is supported by a scholarship from the Chinese Scholarship Council . The authors thank Dr. Julien Louvel for carefully checking and discussing the chemistry paragraphs in the main text and the SI.

Keywords

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

Access to Document

10.1016/j.ejmech.2015.10.032

Cite this

@article{aee55d7381ab4e23bc26ec1eca2b075e,

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

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.",

keywords = "Antiarrhythmia, K11.1 blockers, K11.1(hERG) channel, Negative allosteric modulator, Radioligand binding assay",

author = "Zhiyi Yu and {Van Veldhoven}, {Jacobus P.D.} and {'T Hart}, {Ingrid M.E.} and Kopf, {Adrian H.} and Heitman, {Laura H.} and Ijzerman, {Adriaan P.}",

note = "Funding Information: Zhiyi Yu is supported by a scholarship from the Chinese Scholarship Council . The authors thank Dr. Julien Louvel for carefully checking and discussing the chemistry paragraphs in the main text and the SI. Publisher Copyright: {\textcopyright} 2015 Elsevier Masson SAS. All rights reserved.",

year = "2015",

month = dec,

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doi = "10.1016/j.ejmech.2015.10.032",

language = "English",

volume = "106",

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journal = "European Journal of Medicinal Chemistry",

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T1 - Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel

AU - Yu, Zhiyi

AU - Van Veldhoven, Jacobus P.D.

AU - 'T Hart, Ingrid M.E.

AU - Kopf, Adrian H.

AU - Heitman, Laura H.

AU - Ijzerman, Adriaan P.

N1 - Funding Information: Zhiyi Yu is supported by a scholarship from the Chinese Scholarship Council . The authors thank Dr. Julien Louvel for carefully checking and discussing the chemistry paragraphs in the main text and the SI. Publisher Copyright: © 2015 Elsevier Masson SAS. All rights reserved.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

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KW - K11.1 blockers

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KW - Radioligand binding assay

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