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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.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lee J,Lee J,Kang M,Shin M,Kim JM,Kang SU,Lim JO,Choi HK,Suh YG,Park HG,Oh U,Kim HD,Park YH,Ha HJ,Kim YH,Toth A,Wang Y,Tran R,Pearce LV,Lundberg DJ,Blumberg PM

doi

10.1021/jm030089u

keywords:

subject

Has Abstract

pub_date

2003-07-03 00:00:00

pages

3116-26

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

46

pub_type

杂志文章

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