title: N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor.
abstract: Isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor (VR1) agonists with the alkylsulfonamido group provides a series of compounds which are effective antagonists to the action of the capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. In particular, compound 61, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea was a full antagonist against capsaicin, displayed a K(i) value of 7.8 nM (compared to 520 nM for capsazepine and 4 nM for 5-iodoRTX), and showed excellent analgesic activity in mice. Structure-activity analysis of the influence of modifications in the A- and C-regions of 4-methylsulfonamide ligands on VR1 agonism/antagonism indicated that 3-fluoro substitution in the A-region and a 4-tert-butylbenzyl moiety in the C-region favored antagonism, whereas a 3-methoxy group in the A-region and 3-acyloxy-2-benzylpropyl moieties in the C-region favored agonism.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea. jeewoo@snu.ac.kr
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.forename: Myungshim
authors.initials: M
authors.lastname: Kang
authors.forename: Myoungyoup
authors.initials: M
authors.lastname: Shin
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Kang
authors.forename: Ju-Ok
authors.initials: JO
authors.lastname: Lim
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Choi
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.forename: Hyeung-Geun
authors.initials: HG
authors.lastname: Park
authors.forename: Uhtaek
authors.initials: U
authors.lastname: Oh
authors.forename: Hee-Doo
authors.initials: HD
authors.lastname: Kim
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Ha
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Attila
authors.initials: A
authors.lastname: Toth
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Tran
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lundberg
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000700:Analgesics; D008024:Ligands; C476142:N-(2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl)-N'-(3-fluoro-4-(methylsulfonylamino)benzyl)thiourea; D011955:Receptors, Drug; D013449:Sulfonamides; D013890:Thiourea; D002211:Capsaicin; D002118:Calcium