Some pharmacological properties of cyclic and linear analogs obtained by substituting each residue of an oxytocin antagonist with D-tryptophan.
Some pharmacological properties of cyclic and linear analogs obtained by substituting each residue of an oxytocin antagonist with D-tryptophan.
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DOI：
10.1111/j.1399-3011.1991.tb01425.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：
G. Flouret;W. Brieher;T. Majewski;K. Mahan;L. Wilson
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作者：
G. Flouret;W. Brieher;T. Majewski;K. Mahan;L. Wilson
我们从[Pmp1，D-Trp2，Arg8]催产素序列中合成了10个类似物（1-10），（亲本拮抗剂或PA）， （Pmp = β， β -五亚甲基- β -巯基丙酸），这是一种有效的拮抗剂（pA2 = 7.77）催产素（OT）在大鼠的子宫紧张性作用，我们的子宫紧张性实验确定。通过用d -色氨酸替代PA序列中除2位残基外的每个残基，设计了以下8个类似物：Ac-D-Trp-D-Trp-Ile-Gln-Asn-Val-Pro- Arg-Gly-NH2， (1)；[Pmp1,D-Trp(For)2,Arg8] OT, (2)；[Pmp1,D-Trp2,D-Trp3,Arg8] OT, (3)；[Pmp1,D-Trp2,D-Trp4,Arg8] OT, (4)；[Pmp1,D-Trp2,D-Trp5,Arg8] OT, (5)；Aaa-D-Trp-Ile-Gln-Asn-D-Trp-Pro-Arg- Gly-NH2, (6)；[Pmp1,D-Trp2,D-Trp7,Arg8] OT, (7)；[Pmp1,D-Trp2,D-Trp8] OT, (8)；[Pmp1,D-Trp2,Arg8,D-Trp9] OT, (9)；[Pmp1,D-Trp2,Arg8,D-Trp(For)9] OT,（10）。为了避免游离硫醇基团，在类似物1中选择Val6代替Cys，在类似物6中选择Aaa1 （Aaa = 1-adamantaneacetic acid）代替Pmp1。在线性类似物中，1是无活性的OT拮抗剂，6是非常差的拮抗剂，pA2 = 5.66，但比我们之前报道的pA2 = 5.33的aaa - d - trp - ile - gln - asn - val -亲arg - gly - nh2更有效。D-Trp(For)2 pA2 = 7.37的类比物2弱于PA，说明甲酰降低了效力。类似物3和4比PA弱得多，类似物5无活性。因此，除了位置2之外，D-Trp在PA的环序列中是不受欢迎的。（摘要删节250字）
We synthesized 10 analogs (1-10) derived from the sequence of [Pmp1,D-Trp2,Arg8]oxytocin, (parent antagonist or PA), (Pmp = beta,beta-pentamethylene-beta-mercaptopropionic acid) which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats, as determined in our uterotonic assay. Eight of the following analogs were designed by replacement of each residue in the PA sequence, other than the residue at position 2, with D-tryptophan: Ac-D-Trp-D-Trp-Ile-Gln-Asn-Val-Pro- Arg-Gly-NH2, (1); [Pmp1,D-Trp(For)2,Arg8] OT, (2); [Pmp1,D-Trp2,D-Trp3,Arg8] OT, (3); [Pmp1,D-Trp2,D-Trp4,Arg8] OT, (4); [Pmp1,D-Trp2,D-Trp5,Arg8] OT, (5); Aaa-D-Trp-Ile-Gln-Asn-D-Trp-Pro-Arg- Gly-NH2, (6); [Pmp1,D-Trp2,D-Trp7,Arg8] OT, (7); [Pmp1,D-Trp2,D-Trp8] OT, (8); [Pmp1,D-Trp2,Arg8,D-Trp9] OT, (9); [Pmp1,D-Trp2,Arg8,D-Trp(For)9] OT, (10). To avoid free mercaptan groups, Val6 was chosen in analog 1 instead of Cys and Aaa1 (Aaa = 1-adamantaneacetic acid) in analog 6 instead of Pmp1. Of the linear analogs, 1 was inactive as an OT antagonist and 6 was a very poor antagonist, with a pA2 = 5.66, but it was more potent than Aaa-D-Trp-Ile-Gln-Asn-Val-Pro-Arg-Gly-NH2, which has a pA2 = 5.33, as we had previously reported. Analog 2, featuring D-Trp(For)2, pA2 = 7.37, was weaker than PA, indicating that the formyl group lowers potency. Analogs 3 and 4 were much weaker than PA, and analog 5 was inactive. Hence, other than at position 2, D-Trp is undesirable in the ring sequence of PA.(ABSTRACT TRUNCATED AT 250 WORDS)