Inverse agonist activity of angiotensin II type 1 receptor blockers

血管紧张素II(AngII)1型受体(AT_1)是一种G蛋白偶联受体，在负荷性心肌肥厚的发生发展中起重要作用。我们先前报道，机械应激可通过非依赖血管紧张素转换酶激活AT_1受体来诱导肥大反应，这种激活可被具有反向激动剂活性的AT_1受体阻滞剂(ARB)所抑制。在这项研究中，我们寻找了AT_1受体的关键区域，它负责机械拉伸诱导的激活。此外，我们还比较了4种具有相同联苯四唑环结构的亲水性ARB的反向激动剂活性，并考察了化学结构与ARB反向激动剂活性之间的关系。我们首次构建了一系列由AT_1受体和内皮素-1 A型受体组成的嵌合体受体，这是一种G蛋白偶联受体，对机械应激没有反应性。检查…嵌合体受体中ERKs激活的进一步研究表明，Lys199-Ser252区域是血管紧张素转换酶诱导受体激活的关键区域。然而，同样的方法未能确定对机械应激诱导的受体激活至关重要的区域。我们推测嵌合体受体中可能存在二硫键的异常形成，机械应激可能导致嵌合体受体的构象改变。当检测到对AT_1-N111G突变受体的构成活性或对机械应激诱导的AT_1受体激活的抑制作用时，氯沙坦表现出轻微的反向激动剂活性，而Valsartan、坎地沙坦和奥美沙坦则表现出中等到过度的反向激动剂活性。强效反向激动剂中咪唑环上的羧基的存在表明，化学结构在显示有效反向激动剂活性方面起着重要作用。进一步分析ARB中AT_1受体的结构与功能，探讨其化学结构与反向激动剂活性之间的关系，将有助于建立具有更强反向激动剂活性和更强的抗器官损伤作用的理想ARB。较少

The angiotensin II (AngII) type 1 (AT_1) receptor is a G protein-coupled receptor that plays a crucial role in the development of load-induced cardiac hypertrophy. We previously reported that mechanical stress can induce hypertrophic responses by activating AT_1 receptor independently of AngII, and that this activation can be inhibited by an AT_1 receptor blocker (ARB) with inverse agonist activity. In this study, we searched for the critical region of the AT_1 receptor, which is responsible for mechanical stretch-induced activation. In addition, we compared the inverse agonist activity in 4 kinds of hydrophilic ARBs, which share the bi-phenyl-tetrazole ring structure in common, and examined the relationship between the chemical structure and the inverse agonist activity in ARBs.We first constructed a series of chimera receptors consisting of the AT_1 receptor and the endothelin-1 type A receptor, which is a G protein-coupled receptor without responsiveness to mechanical stress. Examin … More ation of ERKs activation in chimera receptors revealed that a region ranging from Lys199 to Ser252 was critical for AngII-induced receptor activation. However, the same approach failed to identify the region that is critical for mechanical stress-induced receptor activation. We suppose that disulfide bonds might be aberrantly formed in chimera receptors, and that mechanical stress might induce undefined conformational change of chimera receptors.Losartan showed mild inverse agonist activity, while valsartan, candesartan, and olmesartan showed moderate to exceeding inverse agonist activities, when the inhibitory effects either on constitutive activity of the AT_1-N111G mutant receptor or on mechanical stress-induced activation of the AT_1 receptor were examined. The presence of the carboxyl group at the imidazole ring in the potent inverse agonists suggested that the chemical structure plays an important role in exhibiting the potent inverse agonist activity. Further analysis of structure-function of the AT_1 receptor and investigation of the relationship between the chemical structure and the inverse agonist activity in ARBs will be of help for the establishment of an ideal ARB with more potent inverse agonist activity and more protective effect against the organ damages. Less