Design of more potent antagonists of the antidiuretic responses to arginine-vasopressin.
Design of more potent antagonists of the antidiuretic responses to arginine-vasopressin.
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设计更有效的精氨酸-加压素抗利尿反应拮抗剂。
DOI：
10.1021/jm00343a009
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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;Olma,A;Klis,WA;Kolodziejczyk,AM;Seto,J;Sawyer,WH
作为旨在设计针对精氨酸-加压素 (AVP) 抗利尿反应的更有效和选择性拮抗剂的计划的一部分，我们在之前报道的八种针对 Avp 的抗利尿和加压反应的 O-烷基-L-酪氨酸拮抗剂中的第 2 位取代了 O-烷基-D-酪氨酸（其中烷基=甲基、乙基、异丙基或正丙基）。我们还在两种具有弱抗利尿激动活性的血管加压拮抗剂[l-(d-巯基-| 8, d-环戊亚甲基丙酸), 4-缬氨酸, 8-Drarginine]加压素[d(CH2) 5VDAVP]及其L-精氨酸异构体[d(CH2) 5VAVP]中用D-酪氨酸取代了L-酪氨酸。固相法合成的10个类似物如下：1、d(CH2)5-D-Tyr(Me)VDAVP； 2、d(CH2)6-D-Tyr(Et)VDAVP； 3、d(CH2)6-D-Tyr(i-Pr)VDAVP； 4、d(CH2)6-D-Tyr(n-Pr)VDAVP； 5、d(CH2)6-D-Tyr(Me)VAVP； 6、d(CH2)6-D-Tyr(Et)VAVP； 7、d(CH2)5-D-Tyr(n-Pr)VAVP； 8，d-(CH2gD-Tyrlt-PrWAVP；9，diCH2-D-TyrVDAVP；10，d(CH2)5-D-TyrVAVP。测试了这些类似物在大鼠抗利尿剂和大鼠血管加压系统中的激动和拮抗活性。所有十种 D-酪氨酸类似物都具有短暂的弱抗利尿活性（0.004-0.05）后续剂量的 A VP 可逆性拮抗 1-3 小时，具体取决于拮抗剂的剂量。 7.77±0.07；6，7.81±0.11；8，7.61±0.06；9，7.03±0.05；10，7.51±0.08。 O-烷基-L-酪氨酸异构体作为抗利尿剂拮抗剂。由于O-烷基-L-酪氨酸类似物的血管升压效力已减弱或几乎保持不变，因此这些类似物相对于其各自的O-烷基-L-酪氨酸类似物表现出选择性增加其抗利尿/抗血管升压比率。 (CH2) 6VDAVP 和 d (CH2) 5VAVP 将这些弱抗利尿激动剂转化为 Avp 抗利尿反应的强效拮抗剂，这一点非常重要，特别是考虑到未烷基化酪氨酸类似物的合成相对容易且产量比烷基化酪氨酸类似物高得多。这里提出的研究结果对于设计更有效和选择性的药物也具有明显的潜力。抗利尿拮抗剂。
As part of a program aimed at designing more potent andselective antagonists of the antidiuretic responses to arginine-vasopressin (AVP), we substituted O-alkyl-D-tyrosine (where alkyl= methyl, ethyl, isopropyl, or n-propyl) at position 2 in our eight previously reported O-alkyl-L-tyrosine antagonists of antidiuretic and vasopressorresponses to Avp. We also substituted D-tyrosine for L-tyrosine in two vasopressor antagonists with weak antidiuretic agonistic activity,[l-(d-mercapto-| 8, d-cyclopentamethylenepropionicacid), 4-valine, 8-Drarginine] vasopressin [d (CH2) 5VDAVP] and its L-arginine isomer [d (CH2) 5VAVP]. The ten analogues, synthesized by the solid-phase method, are as follows:1, d (CH2) 5-D-Tyr (Me) VDAVP; 2, d (CH2) 6-D-Tyr (Et) VDAVP; 3, d (CH2) 6-D-Tyr (i-Pr) VDAVP; 4, d (CH2) 6-D-Tyr (n-Pr) VDAVP; 5, d (CH2) 6-D-Tyr (Me) VAVP; 6, d (CH2) 6-D-Tyr (Et) VAVP; 7, d (CH2) 5-D-Tyr (n-Pr) VAVP; 8, d-(CH^ gD-Tyrlt-PrWAVP; 9, diCH^-D-TyrVDAVP; 10, d (CH2) 5-D-TyrVAVP. These analogues were tested for agonistic and antagonistic activities in rat antidiuretic and rat vasopressor systems. All ten D-tyrosine analogues possess transient weak antidiuretic activities (0.004-0.05 U/mg). Subsequent doses of A VP are reversibly antagonized for 1-3 h, depending on the dose of the antagonist. They exhibit the following antiantidiuretic pA2 values: 1, 7.19±0.11; 2, 7.59±0.04; 3, 7.51±0.06; 4, 7.60±0.05; 5, 7.77±0.07; 6, 7.81±0.07; 7, 7.66±0.11; 8, 7.61±0.06; 9, 7.03±0.05; 10, 7.51±0.08. They are all effective antagonists of vasopressor responses to A VP. Analogues1-8 are two to ten times more potent than their respective O-alkyl-L-tyrosineisomers as antidiuretic antagonists. Since the vasopressor potencies of the O-alkyl-L-tyrosine analogues have either diminished or remained virtually unchanged, these analogues exhibit a selective increase in their antiantidiuretic/antivasopressor ratios with respect to their respective O-alkyl-L-tyrosine analogues. The finding that the substitution of an unalkylated D-tyrosine for L-tyrosine in d (CH2) 6VDAVP and d (CH2) 5VAVP converts these weak antidiuretic agonists into potent antagonists of antidiuretic responses to Avp is highly significant, especially in view of the relative ease of synthesis and much higher yields of unalkylated vs. alkylated tyrosine analogues. These ten new analogues are potentially useful as pharmacological tools and as therapeutic agents. The findings presented here have also obvious potential for thedesign of even more potent and selective antidiuretic antagonists.