Design of more potent and selective antagonists of the antidiuretic responses to arginine-vasopressin devoid of antidiuretic agonism.
Design of more potent and selective antagonists of the antidiuretic responses to arginine-vasopressin devoid of antidiuretic agonism.
复制标题
设计更有效和选择性的精氨酸-加压素抗利尿反应拮抗剂，但不具有抗利尿激动作用。
DOI：
10.1021/jm00346a016
复制
发表时间：
1982
影响因子：
7.3
通讯作者：
Sawyer,WH
中科院分区：
文献类型：
--
作者：
Manning,M;Klis,WA;Olma,A;Seto,J;Sawyer,WH
[1-（β-巯基-β，d-环戊亚甲基丙酸），4-缬氨酸]精氨酸-加压素，d（CH 2）5VAVP的2位D-酪氨酸的取代将这种弱的抗利尿激动剂和血管加压反应的拮抗剂转变为抗利尿反应的有效拮抗剂。然而，d（CH 2）6-D-TyrVAVP与其它报道的抗利尿反应拮抗剂一样，保留了一些抗利尿激动活性。它也是一种相对较强的血管加压和催产反应拮抗剂。为了（a）提高抗利尿反应拮抗剂的特异性，（B）消除残余激动活性和增强拮抗效力，（c）帮助描述抗利尿拮抗作用所需的2位结构特征，我们用固相法合成了8个新的2位取代的类似物：1，d（CH 2）6-D-PheVAVP; 2，d（CH 2）6-D-PheVDAVP; 3，d-（CH 2）sD-IleVAVP; 4，d（CH 2）6-D-LeuVAVP; 5，d（CH 2）6-D-ValVAVP; 6，d（CH 2）6-D-AlaVAVP; 7，d（CH 2）6GlyVAVP; 8，d（CH 2）5-D-ArgVAVP。这些类似物进行了测试agonisticand拮抗活性的抗利尿剂，血管加压药，催产素测定大鼠。类似物1、3、4和5在这些测定中没有表现出激动活性。这四个类似物，以及类似物2，有效地拮抗AVP的抗利尿反应。它们的抗利尿剂pA 2值如下：1，8.07±0.09; 2，7.07±0.1; 3，7.98±0.05; 4，7.79±0.12; 5，7.48±0.06。类似物6 -8是弱抗利尿剂激动剂，没有表现出可检测的抗利尿活性。类似物3-8显示作为血管加压和催产反应的拮抗剂的效力大大降低。因此，类似物3-5作为抗利尿反应的拮抗剂显示出比任何先前报道的更大的特异性。类似物1和3也是迄今报道的抗利尿反应的最有效的拮抗剂。这些类似物的抗利尿作用和特异性的结合使其成为研究AVP在实验动物和人体中引起水潴留的作用的有用工具，它们也可以作为设计更有效和选择性的抗利尿拮抗剂的原型。ADH抗利尿作用的有效和特异性拮抗剂可能对治疗各种临床情况下的水潴留有价值。
Substitution of D-tyrosine at position 2 of [1-(/3-mercapto-/3, d-cyclopentamethylenepropionic acid), 4-valine] arginine-vasopressin, d (CH2) 5VAVP, turned this weak antidiuretic agonist and antagonist of vasopressor responses into an effective antagonist of the antidiuretic response. d (CH2) 6-D-TyrVAVP, however, like other reported antagonists of the antidiuretic response, retains some antidiuretic agonistic activity. It is also a relatively strong antagonist of vasopressor and oxytocic responses. In attempting (a) to increase the specificity of antagonists of the antidiuretic response,(b) to eliminate residual agonistic activity andenhance antagonistic potency, and (c) to help delineate structural features at position 2 required for antidiuretic antagonism, we have synthesizedeight new analogues substituted at position 2 by the solid-phase method: 1, d (CH2) 6-D-PheVAVP; 2, d (CH2) 6-D-PheVDAVP; 3, d-(CH2) sD-IleVAVP; 4, d (CH2) 6-D-LeuVAVP; 5, d (CH2) 6-D-ValVAVP; 6, d (CH2) 6-D-AlaVAVP; 7, d (CH2) 6GlyVAVP; 8, d (CH2) 5-D-ArgVAVP. These analogues were tested for agonisticand antagonistic activities by antidiuretic, vasopressor, and oxytocic assays in rats. Analogues 1, 3, 4, and 5 exhibit no agonistic activities in these assays. These four analogues, as well as analogue 2, effectively antagonize antidiuretic responses toAVP. Their antiantidiuretic pA2 values are as follows: 1, 8.07±0.09; 2, 7.07±0.1; 3, 7.98±0.05; 4, 7.79±0.12; 5, 7.48±0.06. Analogues6-8 are weak antidiuretic agonists and exhibit no detectable antiantidiuretic activity. Analogues 3-8 show greatly reduced potencies as antagonists of vasopressor and oxytocic responses. Thus, analogues 3-5 show much greater specificity as antagonists of the antidiuretic response than any previously reported. Analogues 1 and 3 are also the most potent antagonists of the antidiuretic response yet reported. The combination of increased antiantidiuretic potency and specificity shouldmake these analogues useful tools for studies on the role of AVP in causing water retention in experimental animals and in man. They may also serve as prototypes for the design of even more potent and selective antidiuretic antagonists. Potent and specific antagonists of the antidiuretic action of ADH could be valuable for treating water retention in a variety of clinical situations.