Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

Dong Wook Kang; Hyung Chul Ryu; Jeewoo Lee; Krystle A. Lang; Vladimir A. Pavlyukovets; Larry V. Pearce; Tetsurou Ikeda; Jozsef Lazar; Peter M. Blumberg

doi:10.1016/j.bmcl.2006.09.059

Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

Dong Wook Kang, Hyung Chul Ryu, Jeewoo Lee, Krystle A. Lang, Vladimir A. Pavlyukovets, Larry V. Pearce, Tetsurou Ikeda, Jozsef Lazar, Peter M. Blumberg

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with K_i (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.

Original language	English
Pages (from-to)	214-219
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2006.09.059
State	Published - Jan 1 2007

Bibliographical note

Funding Information:
This work was supported by Grant R01-2004-000-10132-0 from the Basic Research Program of the Korea Science and Engineering Foundation and this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Matthew A. Morgan, Andrew K. Tao, and Christopher B. Ryder for technical assistance.

Keywords

Capsaicinoid
Halogenation
Resiniferatoxin
TRPV1 agonist
TRPV1 antagonist

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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title = "Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin",

abstract = "Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with Ki (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.",

keywords = "Capsaicinoid, Halogenation, Resiniferatoxin, TRPV1 agonist, TRPV1 antagonist",

author = "Kang, {Dong Wook} and Ryu, {Hyung Chul} and Jeewoo Lee and Lang, {Krystle A.} and Pavlyukovets, {Vladimir A.} and Pearce, {Larry V.} and Tetsurou Ikeda and Jozsef Lazar and Blumberg, {Peter M.}",

note = "Funding Information: This work was supported by Grant R01-2004-000-10132-0 from the Basic Research Program of the Korea Science and Engineering Foundation and this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Matthew A. Morgan, Andrew K. Tao, and Christopher B. Ryder for technical assistance.",

year = "2007",

month = jan,

day = "1",

doi = "10.1016/j.bmcl.2006.09.059",

language = "English",

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T1 - Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

AU - Kang, Dong Wook

AU - Ryu, Hyung Chul

AU - Lee, Jeewoo

AU - Lang, Krystle A.

AU - Pavlyukovets, Vladimir A.

AU - Pearce, Larry V.

AU - Ikeda, Tetsurou

AU - Lazar, Jozsef

AU - Blumberg, Peter M.

N1 - Funding Information: This work was supported by Grant R01-2004-000-10132-0 from the Basic Research Program of the Korea Science and Engineering Foundation and this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Matthew A. Morgan, Andrew K. Tao, and Christopher B. Ryder for technical assistance.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with Ki (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.

AB - Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with Ki (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.

KW - Capsaicinoid

KW - Halogenation

KW - Resiniferatoxin

KW - TRPV1 agonist

KW - TRPV1 antagonist

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JO - Bioorganic and Medicinal Chemistry Letters

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Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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