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N-(3-acyloxy-2-benzylpropyl)-N '-[4-(methylsulfonylamino)benzyl]thiourea analogues: Novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor

Authors
Lee, JLee, JKang, MShin, MKim, JMKang, SULim, JOChoi, HKSuh, YGPark, HGOh, UKim, HDPark, YHHa, HJKim, YHToth, AWang, YTran, RPearce, LVLundberg, DJBlumberg, PM
Issue Date
3-Jul-2003
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF MEDICINAL CHEMISTRY, v.46, no.14, pp.3116 - 3126
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
Volume
46
Number
14
Start Page
3116
End Page
3126
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/16177
DOI
10.1021/jm030089u
ISSN
0022-2623
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.
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