N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor.
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.
Lee
Jeewoo
J
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea. jeewoo@snu.ac.kr
Lee
Jiyoun
J
Kang
Myungshim
M
Shin
Myoungyoup
M
Kim
Ji-Min
JM
Kang
Sang-Uk
SU
Lim
Ju-Ok
JO
Choi
Hyun-Kyung
HK
Suh
Young-Ger
YG
Park
Hyeung-Geun
HG
Oh
Uhtaek
U
Kim
Hee-Doo
HD
Park
Young-Ho
YH
Ha
Hee-Jin
HJ
Kim
Young-Ho
YH
Toth
Attila
A
Wang
Yun
Y
Tran
Richard
R
Pearce
Larry V
LV
Lundberg
Daniel J
DJ
Blumberg
Peter M
PM
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
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