化学
卡普萨平
立体化学
辣椒素
敌手
中国仓鼠卵巢细胞
对抗
硫脲
兴奋剂
受体
TRPV1型
生物化学
有机化学
瞬时受体电位通道
作者
Jeeyeon Lee,Jiyoun Lee,Myungshim Kang,Moon Sam Shin,Jimin Kim,Sang-Uk Kang,Ju-Ok Lim,Ho Jin Choi,Young‐Ger Suh,Hyeung‐geun Park,Uhtaek Oh,Hee‐Doo Kim,Young-Ho Park,Hee-Jin Ha,Young‐Ho Kim,Attila Tóth,Yun Wang,Richard Tran,Larry V. Pearce,Daniel J. Lundberg,Peter M. Blumberg
摘要
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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