Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation
Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation
复制标题
DOI：
10.1152/ajpheart.00831.2001
复制
发表时间：
2003-01-01
影响因子：
4.8
通讯作者：
Campbell, WB
中科院分区：
文献类型：
--
作者：
Falck, JR;Krishna, UM;Campbell, WB
环氧二十碳三烯酸(EETs)是一种内皮来源的二十烷酸类化合物，它能激活钾通道，使膜超极化，并引起松弛。我们测试了19个14，15-EET的类似物对血管张力的影响，以确定活动所需的结构特征。14，15-EET对牛冠状动脉环具有浓度依赖性的松弛作用(ED50=10(-6)M)。将羧基改为醇消除了扩张剂的活性，而14，15-EET-甲基酯和14，15-EET-甲磺酰亚胺保持了全部活性。缩短羧基和环氧基之间的距离会降低激动剂的效力和活性。所有三个双键的去除都降低了效力。具有Delta8双键的类似物具有完全的活性和效力。然而，仅含有Delta5或Delta11双键的类似物的效力有所降低。环氧氧转化为硫磺或氮气会导致活性丧失。14(S)，15(R)-EET强于14(R)，15(S)-EET，14，15-(顺)-EET强于14，15(反式)-EET。这些研究表明，牛冠状动脉松弛所需的14，15-EET的结构特征包括碳-1酸性基团、Delta8双键和14(S)，15(R)-(顺)-环氧基团。
Epoxyeicosatrienoic acids (EETs) are endothelium-derived eicosanoids that activate potassium channels, hyperpolarize the membrane, and cause relaxation. We tested 19 analogs of 14,15-EET on vascular tone to determine the structural features required for activity. 14,15-EET relaxed bovine coronary arterial rings in a concentration-related manner (ED50=10(-6) M). Changing the carboxyl to an alcohol eliminated dilator activity, whereas 14,15-EET-methyl ester and 14,15-EET-methylsulfonimide retained full activity. Shortening the distance between the carboxyl and epoxy groups reduced the agonist potency and activity. Removal of all three double bonds decreased potency. An analog with a Delta8 double bond had full activity and potency. However, the analogs with only a Delta5 or Delta11 double bond had reduced potency. Conversion of the epoxy oxygen to a sulfur or nitrogen resulted in loss of activity. 14(S), 15(R)-EET was more potent than 14(R), 15(S)-EET, and 14,15-(cis)-EET was more potent than 14,15(trans)-EET. These studies indicate that the structural features of 14,15-EET required for relaxation of the bovine coronary artery include a carbon-1 acidic group, a Delta8 double bond, and a 14(S), 15(R)-(cis)-epoxy group.