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

Research output: Contribution to journalArticle

8 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 languageEnglish (US)
Pages (from-to)690-698
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2009
Externally publishedYes

Keywords

  • Resiniferatoxin
  • TRPV1 agonist

ASJC Scopus subject areas

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

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  • Cite this

    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