Design and synthesis of potent in vivo antagonists of oxytocin.
Design and synthesis of potent in vivo antagonists of oxytocin.
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DOI：
10.1111/j.1399-3011.1980.tb02962.x
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发表时间：
2009-01
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影响因子：
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通讯作者：
K. Bańkowski;M. Manning;J. Seto;J. Haldar;Wilbur H. Sawyer
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文献类型：
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作者：
K. Bańkowski;M. Manning;J. Seto;J. Haldar;Wilbur H. Sawyer
我们先前已经证明，在体内，8-鸟氨酸和2-O-甲基酪氨酸与[1-脱氨青霉胺]催产素(DPOT)单独或联合使用可增强对催产素的拮抗作用。为了探讨含有较大烷基取代基的dPOT类似物中的这些取代对1位β碳和2位酪氨酸残基的影响，合成了以下6个类似物：[1-(β-巯基-β，β-二乙基丙酸)，8-鸟氨酸]血管催产素(1，dEt2OVT)；(2，d(CH2)5OVT)：[1-β-巯基-β，β-二乙基丙酸]，2-O-甲基酪氨酸，8-鸟氨酸]血管生成素[3，dEt2 Tyr(Me)OVT]；2-O-甲基酪氨酸，8-鸟氨酸]血管催产素[5，d(CH2)5-Tyr(Me)OVT]：[1-β-巯基-β，β-环戊亚甲基丙酸)，2-O-甲基酪氨酸，8-鸟氨酸]血管催产素[6，d(CH2)5 Tyr(ET)OVT]。所需的保护中间体是通过固相合成和溶液中单独的8+1偶联反应合成的。在无镁离子、0.5 mM镁离子存在和在位条件下，所有六个类似物都能拮抗催产素对大鼠子宫的作用。它们还可以对抗催产素的排乳反应和精氨酸加压素的加压反应，而且它们的抗利尿活性都很低。化合物3和5的PA2值分别为7.35+/-0.08和7.37+/-0.17，是迄今为止报道的体内最有效的催产素拮抗剂。
We have previously shown that the substitution of 8-ornithine and 2-O-methyltyrosine alone and in combination in [1-deaminopenicillamine] oxytocin (dPOT) brought about enhancements in antagonistic potencies to responses to oxytocin in vivo. To explore the effects of these substitutions in analogs of dPOT containing larger alkyl substitutents on the beta carbon at position 1 and on the tyrosine residue at position two, the following six analogs were synthesized: [1-(beta-mercapto-beta, beta-diethylpropionic acid), 8-ornithine] vasotocin (1, dEt2OVT); (1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 8-ornithine] vasotocin (2, d(CH2)5OVT): [1-beta-mercapto-beta, beta-diethylpropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [3, dEt2 Tyr(Me)OVT]; [1-(beta-mercapto-beta, beta-diethylpropionic acid), 2-O-ethyltyrosine, 8-ornithine]vasotocin [4, dEt2 Tyr(Et)OVT]; [1-beta-mercapto-beta', beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [5, d(CH2)5 Tyr(me)OVT]: [1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine, 8-ornithine]vasotocin [6,d(CH2)5 Tyr(Et)OVT]. The required protected intermediates were synthesized by a combination of solid-phase synthesis and by individual 8 + 1 couplings in solution. All six analogs antagonize the actions of oxytocin on the rat uterus in the absence of Mg2+, in the presence of 0.5 mM Mg2+ and in situ. They also antagonize milk ejection responses to oxytocin, and the vasopressor responses to arginine vasopressin, and all have very low antidiuretic activities. With pA2 values of 7.35 +/- 0.08 and 7.37 +/- 0.17, respectively, compounds 3 and 5 are the two most potent in vivo antagonists of oxytocin reported to date.