Lowbridge J, Manning M, Seto J, Haldar J, Sawyer W H
J Med Chem. 1979 May;22(5):565-9. doi: 10.1021/jm00191a019.
As part of a program in which we are attempting to synthesize in vivo antagonists of oxytocin, the following four analogues were synthesized and tested for antagonistic activities in rat uterus and rat vasopressor assay systems: [-(beta-mercapto-beta,beta-diethylpropionic acid), 4-threonine]oxytocin (1, dEt2TOT), [1-beta-mercapto-beta,beta-cyclopenta-methylenepropionic acid), 4-threonine]oxytocin [2, d(CH2)5TOT], [1-deaminopenicillamine,2-O-methyltyrosine]oxytocin [3, dPTyr(Me)OT], and [1-deaminopenicillamine,2-O-methyltyrosine,4-threonine]oxytocin [4, dPTyr(Me)TOT]. The required protected intermediates were synthesized by a combination of solid-phase peptide synthesis and by individual 8 + 1 couplings in solution. All four analogues antagonize the actions of oxytocin on the rat uterus (a) in the absence of Mg2+, (b) in the presence of 0.5 mM Mg2+, and (c) in situ. They exhibit, respectively, the following pA2 values in each of the assay systems a-c: (1) (a) 7.72 +/- 0.11, (b) 7.36 +/- 0.09, (c) 6.47 +/- 0.11; (2) (a) 7.91 +/- 0.13, (b) 7.81 +/- 0.09, (c) 6.94 +/- 0.11; (3) (a) 7.76 +/- 0.12, (b) 7.80 +/- 0.12, (c) 6.86 +/- 0.12; (4) (a) 7.64 +/- 0.14, (b) 7.79 +/- 0.09, (c) 6.84 +/- 0.10. They have the following antivasopressor pA2 values: (1) 6.30 +/- 0.13; (2) 5.86 +/- 0.03; (3) 7.59 +/- 0.05; (4) 7.32 +/- 0.04. Compounds 2-4 are among the most potent in vivo antagonists of oxytocin reported to date.
作为我们试图在体内合成催产素拮抗剂项目的一部分，合成了以下四种类似物，并在大鼠子宫和大鼠升压试验系统中测试了其拮抗活性：[-(β-巯基-β,β-二乙基丙酸),4-苏氨酸]催产素(1,dEt2TOT)、[1-β-巯基-β,β-环戊亚甲基丙酸),4-苏氨酸]催产素[2,d(CH2)5TOT]、[1-脱氨青霉胺,2-O-甲基酪氨酸]催产素[3,dPTyr(Me)OT]和[1-脱氨青霉胺,2-O-甲基酪氨酸,4-苏氨酸]催产素[4,dPTyr(Me)TOT]。所需的保护中间体通过固相肽合成和溶液中的单个8 + 1偶联相结合的方法合成。所有四种类似物均能拮抗催产素对大鼠子宫的作用：(a)在无Mg2+的情况下；(b)在存在0.5 mM Mg2+的情况下；(c)在原位。在每种试验系统a - c中，它们分别具有以下pA2值：(1)(a)7.72±0.11，(b)7.36±0.09，(c)6.47±0.11；(2)(a)7.91±0.13，(b)7.81±0.09，(c)6.94±0.11；(3)(a)7.76±0.12，(b)7.80±0.12，(c)6.86±0.12；(4)(a)7.64±0.14，(b)7.79±0.09，(c)6.84±0.10。它们具有以下抗升压pA2值：(1)6.30±0.13；(2)5.86±0.03；(3)7.59±0.05；(4)7.32±0.04。化合物2 - 4是迄今为止报道的最有效的体内催产素拮抗剂之一。
