Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists

Hyun Kyung Choi; Sun Choi; Yoonji Lee; Dong Wook Kang; Hyung Chul Ryu; Han Joo Maeng; Suk Jae Chung; Vladimir A. Pavlyukovets; Larry V. Pearce; Attila Toth; Richard Tran; Yun Wang; Matthew A. Morgan; Peter M. Blumberg; Jeewoo Lee

doi:10.1016/j.bmc.2008.11.085

Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists

Hyun Kyung Choi, Sun Choi, Yoonji Lee, Dong Wook Kang, Hyung Chul Ryu, Han Joo Maeng, Suk Jae Chung, Vladimir A. Pavlyukovets, Larry V. Pearce, Attila Toth, Richard Tran, Yun Wang, Matthew A. Morgan, Peter M. Blumberg, Jeewoo Lee

Department of Pharmaceutical Sciences

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

10 Scopus citations

Abstract

A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC₅₀ = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region.

Original language	English
Pages (from-to)	690-698
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	2
DOIs	https://doi.org/10.1016/j.bmc.2008.11.085
State	Published - 15 Jan 2009

Bibliographical note

Funding Information:
This research was supported by Grants R11-2007-107-02001-0 and R01-2007-000-20052-0 from the Korea Science and Engineering Foundation (KOSEF), the National Core Research Center program (No. R15-2006-020) of the Ministry of Education, Science and Technology and KOSEF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute.

Keywords

Resiniferatoxin
TRPV1 agonist

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10.1016/j.bmc.2008.11.085

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Choi, H. K., Choi, S., Lee, Y., Kang, D. W., Ryu, H. C., Maeng, H. J., Chung, S. J., Pavlyukovets, V. A., Pearce, L. V., Toth, A., Tran, R., Wang, Y., Morgan, M. A., Blumberg, P. M., & Lee, J. (2009). Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists. Bioorganic and Medicinal Chemistry, 17(2), 690-698. https://doi.org/10.1016/j.bmc.2008.11.085

@article{a6e8ea7286ae4dbb83c35032bcb6b618,

title = "Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists",

abstract = "A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC50 = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region.",

keywords = "Resiniferatoxin, TRPV1 agonist",

author = "Choi, {Hyun Kyung} and Sun Choi and Yoonji Lee and Kang, {Dong Wook} and Ryu, {Hyung Chul} and Maeng, {Han Joo} and Chung, {Suk Jae} and Pavlyukovets, {Vladimir A.} and Pearce, {Larry V.} and Attila Toth and Richard Tran and Yun Wang and Morgan, {Matthew A.} and Blumberg, {Peter M.} and Jeewoo Lee",

note = "Funding Information: This research was supported by Grants R11-2007-107-02001-0 and R01-2007-000-20052-0 from the Korea Science and Engineering Foundation (KOSEF), the National Core Research Center program (No. R15-2006-020) of the Ministry of Education, Science and Technology and KOSEF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute.",

year = "2009",

month = jan,

day = "15",

doi = "10.1016/j.bmc.2008.11.085",

language = "English",

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Choi, HK, Choi, S, Lee, Y, Kang, DW, Ryu, HC, Maeng, HJ, Chung, SJ, Pavlyukovets, VA, Pearce, LV, Toth, A, Tran, R, Wang, Y, Morgan, MA, Blumberg, PM & Lee, J 2009, 'Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists', Bioorganic and Medicinal Chemistry, vol. 17, no. 2, pp. 690-698. https://doi.org/10.1016/j.bmc.2008.11.085

TY - JOUR

T1 - Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists

AU - Choi, Hyun Kyung

AU - Choi, Sun

AU - Lee, Yoonji

AU - Kang, Dong Wook

AU - Ryu, Hyung Chul

AU - Maeng, Han Joo

AU - Chung, Suk Jae

AU - Pavlyukovets, Vladimir A.

AU - Pearce, Larry V.

AU - Toth, Attila

AU - Tran, Richard

AU - Wang, Yun

AU - Morgan, Matthew A.

AU - Blumberg, Peter M.

AU - Lee, Jeewoo

N1 - Funding Information: This research was supported by Grants R11-2007-107-02001-0 and R01-2007-000-20052-0 from the Korea Science and Engineering Foundation (KOSEF), the National Core Research Center program (No. R15-2006-020) of the Ministry of Education, Science and Technology and KOSEF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute.

PY - 2009/1/15

Y1 - 2009/1/15

N2 - A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC50 = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region.

AB - A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC50 = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region.

KW - Resiniferatoxin

KW - TRPV1 agonist

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U2 - 10.1016/j.bmc.2008.11.085

DO - 10.1016/j.bmc.2008.11.085

M3 - Article

C2 - 19135377

AN - SCOPUS:58549087355

SN - 0968-0896

VL - 17

SP - 690

EP - 698

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 2

ER -

Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists

Abstract

Bibliographical note

Keywords

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