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

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10 Scopus citations


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 languageEnglish
Pages (from-to)690-698
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number2
StatePublished - 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.


  • Resiniferatoxin
  • TRPV1 agonist


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