title: Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin.
abstract: Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I>Br>Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with K(i) (as functional antagonist)=23.1 and 30.3 nM in rTRPV1/CHO system, respectively.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: Hyungchul
authors.initials: H
authors.lastname: Ryu
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Krystle A
authors.initials: KA
authors.lastname: Lang
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Pavlyukovets
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Tetsurou
authors.initials: T
authors.lastname: Ikeda
authors.forename: Jozsef
authors.initials: J
authors.lastname: Lazar
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D000818:Animals; D001966:Bromine / Q000737:chemistry; D016466:CHO Cells; D002211:Capsaicin / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D003412:Cricetulus; D006219:Halogens / Q000737:chemistry; D007455:Iodine / Q000737:chemistry; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000819:agonists*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D006219:Halogens; C519010:N-(3-(tert-butylcarbonyloxy)-2-(3,4-dimethylbenzyl)propyl)-N'-(4-hydroxy-2,3-diiodo-5-methoxybenzyl)thiourea; C519011:N-(4-tert-butylbenzyl)-N'-(4-hydroxy-2-bromo-3-iodo-5-methoxybenzyl)thiourea; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D007455:Iodine; D013890:Thiourea; D002211:Capsaicin; D001966:Bromine