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 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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, South Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Choi
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: HyungChul
authors.initials: H
authors.lastname: Ryu
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Pavlyukovets
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Attila
authors.initials: A
authors.lastname: Toth
authors.forename: Richard
authors.initials: R
authors.lastname: Tran
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000819:agonists*
chemical_list: D004224:Diterpenes; D050916:TRPV Cation Channels; C024353:resiniferatoxin; D002118:Calcium