Moore G J, Franklin K J, Nystrom D M, Goghari M H
Can J Physiol Pharmacol. 1985 Aug;63(8):966-71. doi: 10.1139/y85-159.
The desensitizing potencies of angiotensin II (ANG II) analogues modified at positions 1, 2, 4, 7, and 8 have been examined in the rat isolated uterus assay by determining the time of recovery of the half-maximal concentration (EC50) response to angiotensin II after treatment of the tissues with a high dose (10(-5) M) of each analogue for 2 min. The magnitude of the desensitization effect was substituent dependent in the following manner: position 1, sarcosine (Sar) greater than Asp greater than des-Asp; position 2, Arg greater than Sar; position 4, Tyr greater than Tyr(Me) approximately Phe; position 7, 3,4-dehydroproline (Dpr) greater than Pro greater than thioproline (Tpr) greater than Sar; position 8, Ile greater than D-Trp greater than Ala greater than Phe. The "additivity" rule applied to these structure-desensitization relationships and the most potent desensitizer, requiring 3 h for reestablishment of the EC50 response, was [Sar1, Dpr7, Ile8]-ANG II. The desensitizing potencies of these analogues did not correlate with agonist or antagonist activities and demonstrated that the angiotensin-mediated tissue desensitization process has unique structural determinants. Methylation or elimination of the tyrosine hydroxyl group of strong desensitizers virtually eliminated the desensitization effect, implicating the phenoxyl moiety in the mechanism of desensitization. The initial phase of recovery of angiotensin responsiveness after desensitization by several analogues appeared to obey first-order kinetics. The results are discussed in the contexts of both one- and two-site receptor models.
通过在大鼠离体子宫实验中，用高剂量（10⁻⁵ M）的每种类似物处理组织2分钟后，测定对血管紧张素II（ANG II）半数最大浓度（EC50）反应的恢复时间，研究了在第1、2、4、7和8位修饰的血管紧张素II类似物的脱敏效力。脱敏作用的强度取决于取代基，具体如下：第1位，肌氨酸（Sar）＞天冬氨酸（Asp）＞去天冬氨酸（des - Asp）；第2位，精氨酸（Arg）＞肌氨酸（Sar）；第4位，酪氨酸（Tyr）＞酪氨酸甲酯（Tyr(Me)）≈苯丙氨酸（Phe）；第7位，3,4 - 脱氢脯氨酸（Dpr）＞脯氨酸（Pro）＞硫代脯氨酸（Tpr）＞肌氨酸（Sar）；第8位，异亮氨酸（Ile）＞D - 色氨酸（D - Trp）＞丙氨酸（Ala）＞苯丙氨酸（Phe）。“加和性”规则适用于这些结构 - 脱敏关系，最有效的脱敏剂是[Sar¹, Dpr⁷, Ile⁸] - ANG II，其恢复EC50反应需要3小时。这些类似物的脱敏效力与激动剂或拮抗剂活性无关，表明血管紧张素介导的组织脱敏过程具有独特的结构决定因素。强脱敏剂酪氨酸羟基的甲基化或去除几乎消除了脱敏作用，提示苯氧基部分参与脱敏机制。几种类似物脱敏后血管紧张素反应性恢复的初始阶段似乎符合一级动力学。在一位点和两位点受体模型的背景下讨论了结果。
