14,15-EET analogs: characterization of structural requirements for agonist and antagonist activity in bovine coronary arteries
14,15-EET analogs: characterization of structural requirements for agonist and antagonist activity in bovine coronary arteries
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DOI：
10.1016/j.phrs.2003.09.014
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发表时间：
2004-06-01
影响因子：
9.3
通讯作者：
Campbell, WB
中科院分区：
文献类型：
--
作者：
Gauthier, KM;Falck, JR;Campbell, WB
花生四烯酸代谢物有助于调节血管张力，从而调节组织血流。血管内皮通过细胞色素 P450 环氧化酶将花生四烯酸代谢为环氧二十碳三烯酸或 EET。环氧基团的位置可以发生在花生四烯酸的任何双键上，从而产生四种 EET 区域异构体； 5,6-、8,9-、11,12- 和 14,15-EET。在脉管系统中，EET 是细胞信号级联的关键组成部分，最终激活平滑肌钾通道，诱导膜超极化和血管舒张。在一些脉管系统中，例如牛冠状动脉，EET 区域异构体在诱导舒张方面是等效的，而在其他动脉中，特定的 EET 区域异构体会诱导舒张，而其他动脉则不会。因此，双键和/或环氧基团的位置可能改变血管激动剂活性。这一观察结果表明，EET 化学结构的微小变化可以显着影响血管活性。为了探索这一假设，我们合成了一系列 EET 类似物，并表征了它们在牛冠状动脉中的血管舒张剂激动剂和拮抗剂活性。为了配合本章，我们首先回顾牛冠状动脉中 EET 依赖性舒张的机制，以使读者熟悉 EET 在这些动脉中的作用。第二部分是 14,15-EET 类似物的功能表征概要以及血管扩张剂活性所需的结构成分的描述。最后，我们讨论了具有特定 EET 拮抗剂活性的三种 14,15-EET 类似物的表征，并将其与类似的 11, 12-EET 类似物的活性进行了比较。这些研究表明，14,15-EET 分子的特定结构成分对于扩张剂活性至关重要，这些成分的改变会影响激动剂活性并可能赋予拮抗剂特性。 (C) 2004 Elsevier Ltd. 保留所有权利。
Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that Culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. fit this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description Of Structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11, 12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties. (C) 2004 Elsevier Ltd. All rights reserved.