Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D- phenylalanine,4-valine]arginine-vasopressin at position 4.
Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D- phenylalanine,4-valine]arginine-vasopressin at position 4.
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基于 [1-(β-巯基-β,β-环戊亚甲基丙酸),2-D-苯丙氨酸,4-缬氨酸]精氨酸-加压素 4 位修饰，是精氨酸-加压素抗利尿反应的有效拮抗剂。
DOI：
10.1021/jm00365a011
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发表时间：
1983
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;Olma,A;Klis,WA;Seto,J;Sawyer,WH
作为我们试图（a）描述我们先前报道的抗利尿拮抗剂中1-9位抗利尿拮抗作用所需的结构特征和（B）获得具有增强的抗利尿效力和/或选择性的类似物的计划的一部分，我们合成了14种新的抗利尿拮抗剂类似物[1 - 10]。（3-巯基-[3，8-环戊亚甲基丙酸），2-d-苯丙氨酸，4-缬氨酸]精氨酸-加压素[d-（CH 2）6-D-Phe 2 VA VP），其中4位的缬氨酸残基被以下L-氨基酸和甘氨酸替代：lie、Abu、Thr、Ala、Gin、Lys、Cha、Nle、Nva、Phe、Leu、Gly、Tyr和Pro。这些类似物是1，d-（CH 2）5-D-Phe 2，Ile 4 AVP; 2，d（CH 2）6-D-Phe 2，Abu 4 AVP; 3，d（CH 2）6-D-Phe 2，Thr 4 AVP; 4，d（CH 2）6-D-Phe 2，Ala 4 AVP; 5，d（CH 2）5-D-Phe 2 AVP; 6，d（CH 2）6-D-Phe 2，Lys 4 AVP; 7，d（CH 2）6-D-Phe 2，Cha 4 AVP; 8，d（CH2）6-D-Phe2，Nle4AVP; 9，d（CH2）6-D-Phe2，Nva4AVP; 10，d（CH2）6-D-Phe2，Phe4AVP; 11，d（CH2）6-D-Phe2，Leu4AVP; 12，d（CH2）5-D-Phe2，Gly4AVP; 13，d（CH2）5-D-Phe2，Tyr4AVP; 14，d（CH2）8-D-Phe2，Pro4AVP。合成所有这些肽所需的保护中间体通过固相法制备，并通过氨解从树脂上裂解。在用NH3中的Na去封闭并用K3 [Fe（CN）6]氧化后，使用50%HOAc和0.2M HOAc作为洗脱剂，以两步程序在Sephadex G-15上纯化每种肽。在大鼠中通过抗利尿、血管加压和催产测定来测试类似物1-14的激动和拮抗活性。类似物1、2和4-6没有表现出可检测的抗利尿激动活性。除含Pro 4的类似物外，所有类似物均为抗利尿拮抗剂。它们的抗利尿剂pA_2值分别为：1，8.24±0.08; 2，7.96±0.07; 3，7.62±0.09; 4，7.52±0.03; 5，7.21±0.07; 6，7.22±0.12; 7，7.19±0.08; 8，7.12±0.09; 9，6.99±0.06; 10，6.07±0.11; 11，6.07±0.11; 12，5.85±0.05; 13，~ 5.57; 14，弱激动剂（0.004 U/mg）。类似物1-14还拮抗对精氨酸-加压素（AVP）的血管反应和对催产素的体外催产反应。类似物1、2、3和5也显示拮抗对催产素的体内催产反应。这些类似物中的五种（1、2、3、6和7）表现出增强的抗利尿剂/抗升压剂选择性。d（CH_2）_6-D-Phe_2、Lys_4AVP和其它具有侧链官能团的4位类似物可能是有用的共价配体，用其探测AVP肾和血管受体的结构特征。Ile 4AVP（1）的抗利尿“有效剂量”为0.46±0.07 nmol/kg，pA 2值为8.24±0.08，d（CH 2）sD-Phe 2，是迄今报道的最有效的抗利尿拮抗剂。这和一些其他类似物在这里报告应证明是有用的药理学工具的作用（S）的研究中的Avp在水潴留状态的病因学，也可能是有价值的治疗药物治疗人类的这种情况。这些发现也为设计更有效和选择性的抗利尿剂拮抗剂提供了有价值的见解。
As part of a program in which we are attempting (a) to delineate the structural features at positions 1-9 in our previously reported antidiuretic antagonists required for antidiuretic antagonism and (b) to obtain analogues with enhanced antiantidiuretic potency and/or selectivity, we have synthesized 14 new analogues of the antidiuretic antagonist [l-(/3-mercapto-j3 „8-cyclopentamethylenepropionic acid), 2-d-phenylalanine, 4-valine] arginine-vasopressin [d-(CH2) 6-D-Phe2 VA VP), in which the valineresidue at position 4 was replaced by the following L-amino acids and glycine: lie, Abu, Thr, Ala, Gin, Lys, Cha, Nle, Nva, Phe, Leu, Gly, Tyr, and Pro. These analogues are 1, d-(CH2) 5-D-Phe2, Ile4AVP; 2, d (CH2) 6-D-Phe2, Abu4AVP; 3, d (CH2) 6-D-Phe2, Thr4AVP; 4, d (CH2) 6-D-Phe2, Ala4AVP; 5, d (CH2) 5-D-Phe2AVP; 6, d (CH2) 6-D-Phe2, Lys4AVP; 7, d (CH2) 6-D-Phe2, Cha4AVP; 8, d (CH2) 6-D-Phe2, Nle4AVP; 9, d (CH2) 6-D-Phe2, Nva4AVP; 10, d (CH2) 6-D-Phe2, Phe4AVP; 11, d (CH2) 6-D-Phe2, Leu4AVP; 12, d (CH2) 5-D-Phe2, Gly4AVP; 13, d (CH2) 5-D-Phe2, Tyr4AVP; 14, d (CH2) 8-D-Phe2, Pro4AVP. The protected intermediatesrequired for the synthesis of all of these peptides were prepared by the solid-phase method and cleaved from the resin by ammonolysis. Following deblocking with Na inNH3 and oxidizing with K3 [Fe (CN) 6], each peptide was purified on Sephadex G-15 in a two-step procedure using 50% HOAc and 0.2 M HOAc as eluants. Analogues 1-14 were tested for agonistic and antagonistic activities by antidiuretic, vasopressor, and oxytocic assays in rats. Analogues 1, 2, and 4-6 exhibit no detectable antidiuretic agonistic activity. All analogues, with the exception of the Pro4-containing analogue, are antidiuretic antagonists. Their antiantidiuretic pA2 values are as follows: 1, 8.24±0.08; 2, 7.96±0.07; 3, 7.62±0.09; 4, 7.52±0.03; 5, 7.21±0.07; 6, 7.22±0.12; 7, 7.19±0.08; 8, 7.12±0.09; 9, 6.99±0.06; 10, 6.07±0.11; 11, 6.07±0.11; 12, 5.85±0.05; 13,~ 5.57; 14, a weak agonist (0.004 U/mg). Analogues 1-14 also antagonize the vascular responses to arginine-vasopressin (ÁVP) and the invitro oxytocic responses to oxytocin. Analogues 1, 2, 3, and 5 have also been shown to antagonize the in vivo oxytocic responses to oxytocin. Five of these analogues (1, 2, 3, 6, and 7) exhibit enhanced antiantidiuretic/antivasopressor selectivity. d (CH2) 6-D-Phe2, Lys4AVP and other position-4 analogues with side-chain functional groups may be useful covalent ligands with which to probe the structural characteristics of A VP renal and vascular receptors. With an antiantidiuretic “effective dose” of 0.46±0.07 nmol/kg and a pA2 value of 8.24±0.08, d (CH2) sD-Phe2, Ile4AVP (1) appears to be the most potentantidiuretic antagonist reported to date. This and some of the other analogues reported here should prove to be useful pharmacological tools for studies on the role (s) of Avp in the etiology of water retention states and may also be of value as therapeutic agents for the treatment of such conditions in humans. These findings also provide valuable insights for the design of more potent and selective antidiuretic antagonists.