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

Title
Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists
Authors
Choi, Hyun-KyungChoi, SunLee, YoonjiKang, Dong WookRyu, HyungChulMaeng, Han-JooChung, Suk-JaePavlyukovets, Vladimir A.Pearce, Larry V.Toth, AttilaTran, RichardWang, YunMorgan, Matthew A.Blumberg, Peter M.Lee, Jeewoo
Ewha Authors
최선이윤지
SCOPUS Author ID
최선scopus; 이윤지scopus
Issue Date
2009
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN
0968-0896JCR Link
Citation
vol. 17, no. 2, pp. 690 - 698
Keywords
ResiniferatoxinTRPV1 agonist
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS
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 EC(50) = 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. (C) 2008 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2008.11.085
Appears in Collections:
약학대학 > 약학과 > Journal papers
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