Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin.
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.
Kang
Dong Wook
DW
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Ryu
Hyungchul
H
Lee
Jeewoo
J
Lang
Krystle A
KA
Pavlyukovets
Vladimir A
VA
Pearce
Larry V
LV
Ikeda
Tetsurou
T
Lazar
Jozsef
J
Blumberg
Peter M
PM
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
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