Synthetic antagonists of in vivo antidiuretic and vasopressor responses to arginine-vasopressin.
Synthetic antagonists of in vivo antidiuretic and vasopressor responses to arginine-vasopressin.
复制标题
精氨酸-加压素体内抗利尿剂和血管加压剂反应的合成拮抗剂。
DOI：
10.1021/jm00138a012
复制
发表时间：
1981
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;Lammek,B;Kolodziejczyk,AM;Seto,J;Sawyer,WH
[1-（d-巯基-0，R-）-1，3-二氧杂环己基]-1，3-二氧杂环己基的四个类似物环戊亚甲基丙酸）、4-缬氨酸、8-D-精氨酸]加压素[d-（CH 2）5 VDAVP]及其L-精氨酸异构体d（CH 2）6 VAVP的4种类似物，在2位上具有-甲基-、-乙基-、O-异丙基和O-正丙基酪氨酸取代基，通过固相法使用稍微改进的再氧化程序，然后用钠在液氨中解封闭以克服由于不溶性而造成的损失。这些类似物如下：1，d（CH2）5Tyr（Me）VDAVP; 2，d（CH2）6Tyr（Et）VDAVP; 3，d（CH2）5Tyr（n-Pr）VDAVP; 4，d（CH2）6Tyr（n-Pr）VDAVP; 5，d（CH2）5Tyr（Me）VAVP; 6，d（CH2）6Tyr（Et）VAVP; 7，d（CH2）5Tyr（t'-Pr）VAVP; 8，d（CH2）5Tyr（n-Pr）VAVP。这些类似物在大鼠抗利尿和大鼠血管加压试验系统中进行了激动和拮抗活性测试。所有八个类似物引起短暂的抗利尿剂静脉注射时，有效地拮抗抗利尿剂反应，随后注射精氨酸加压素（AVP）。它们表现出以下抗利尿剂pA 2值：1，6.68±0.11; 2，7.10±0.08; 3，6.88±0.07; 4，6.67±0.05; 5，7.35±0.06; 6，7.57±0.06; 7，7.32±0.10; 8，7.29±0.07。它们也是对AVP的血管加压反应的高效拮抗剂，具有在7.86至8.44范围内的抗血管加压剂pA 2值。这些结果表明，在这一系列的O-乙基取代的酪氨酸在位置2是最佳的抗利尿剂potencyand，L-精氨酸是远远上级D-精氨酸在这方面也。因此，d（CH 2）6 Tyr（Et）VAVP具有7.57±0.06的抗利尿剂pA 2，是这八种抗利尿剂拮抗剂中最有效的。这些是第一个已知的有效拮抗剂在体内抗利尿反应AVP。因此，它们是研究AVP在动物和人类正常和病理生理状态下调节水平衡的作用的潜在有用的药理学工具。它们还可作为设计更有效拮抗剂的优良先导化合物，用于治疗继发于抗利尿激素分泌不当的低钠血症（SIADH或Schwartz-Bartter综合征）。
Four analogues of [l-(d-mercapto-0,/?-cyclopentamethylenepropionicacid), 4-valine, 8-D-arginine] vasopressin [d-(CH2) 5VDAVP] and four analogues of its L-arginine isomer d (CH2) 6VAVP with-methyl-,-ethyl-, O-isopropyl, and 0-n-propyltyrosine substituents at position 2 were prepared by the solid-phase method using a slightly modified reoxidation procedure following deblocking with sodium in liquid ammonia to overcome losses due to insolubility. These analogues are the following: 1, d (CH2) 5Tyr (Me) VDAVP; 2, d (CH2) 6Tyr (Et) VDAVP; 3, dlCH^ sTyrli-PrlVDAVP; 4, d (CH2) 6Tyr (n-Pr) VDAVP; 5, d (CH2) 5Tyr (Me) VAVP; 6, d (CH2) 6Tyr (Et) VAVP; 7, d (CH2) 5Tyr (t'-Pr) VAVP; 8, d (CH2) 5Tyr (n-Pr) VAVP. These analogues were tested for agonistic and antagonistic activitiesin rat antidiuretic and rat vasopressor assay systems. All eight analogues cause a transient antidiuresiswhen injected intravenously and effectively antagonize antidiuretic responses to subsequent injections of arginine-vasopressin (AVP). They exhibit the following antiantidiuretic pA2 values: 1, 6.68±0.11; 2, 7.10±0.08; 3, 6.88±0.07; 4, 6.67±0.05; 5, 7.35±0.06; 6, 7.57±0.06; 7, 7.32±0.10; 8, 7.29±0.07. They are also highly effective antagonists of the vasopressor responses to AVP, with antivasopressor pA2 values in the range 7.86 to 8.44. These findings indicate that in this series O-ethyl substitution on the tyrosine at position 2 is optimal for antiantidiuretic potencyand that L-arginine is far superior to D-arginine in this regard also. Thus, d (CH2) 6Tyr (Et) VAVPwith an antiantidiuretic pA2 of 7.57±0.06 is the most potent of these eight antidiuretic antagonists. These are the first known effective antagonists of in vivo antidiuretic responses to AVP. They are, thus, potentially useful pharmacological tools for studies on the roles of AVP in regulating water balance in normíd and pathophysiological states in animals and in humans. They also serve as excellent lead compounds for thedesign of even more potent antagonists for potential therapeutic use for the treatment of hyponatremia secondary to inappropriate secretion of the antidiuretic hormone (SIADH or the Schwartz-Bartter syndrome).