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N-（3-酰氧基-2-苄基丙基）-N'-[4-（甲基磺酰氨基）苄基]硫脲类似物：新型有效的香草酸受体高亲和力拮抗剂和部分拮抗剂。

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

作者信息

Lee Jeewoo, Lee Jiyoun, Kang Myungshim, Shin Myoungyoup, Kim Ji-Min, Kang Sang-Uk, Lim Ju-Ok, Choi Hyun-Kyung, Suh Young-Ger, Park Hyeung-Geun, Oh Uhtaek, Kim Hee-Doo, Park Young-Ho, Ha Hee-Jin, Kim Young-Ho, Toth Attila, Wang Yun, Tran Richard, Pearce Larry V, Lundberg Daniel J, Blumberg Peter M

机构信息

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea.

出版信息

J Med Chem. 2003 Jul 3;46(14):3116-26. doi: 10.1021/jm030089u.

DOI:10.1021/jm030089u
PMID:12825950
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.

摘要

在强效香草酸受体（VR1）激动剂中，用烷基磺酰胺基对等取代酚羟基，得到了一系列化合物，这些化合物可有效拮抗辣椒素对中国仓鼠卵巢（CHO）细胞中异源表达的大鼠VR1的作用。特别地，化合物61，N-[2-(3,4-二甲基苄基)-3-新戊酰氧基丙基]-N'-[3-氟-4-(甲基磺酰胺基)苄基]硫脲是一种对辣椒素的完全拮抗剂，其K(i)值为7.8 nM（相比之下，辣椒平的K(i)值为520 nM，5-碘RTX的K(i)值为4 nM），并且在小鼠中显示出优异的镇痛活性。对4-甲基磺酰胺配体的A区和C区修饰对VR1激动作用/拮抗作用影响的构效关系分析表明，A区的3-氟取代和C区的4-叔丁基苄基部分有利于拮抗作用，而A区的3-甲氧基和C区的3-酰氧基-2-苄基丙基部分有利于激动作用。

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