Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists |
| |
Authors: | Hyun-Kyung Choi Sun Choi Yoonji Lee Dong Wook Kang HyungChul 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 |
| |
Affiliation: | 1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, South Korea;2. College of Pharmacy, Division of Life and Pharmaceutical Sciences, and National Core Research Center for Cell Signaling and Drug Discovery, Ewha Womans University, Seoul 120-750, South Korea;3. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MA 20892, USA |
| |
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: | |
本文献已被 ScienceDirect 等数据库收录! |
|