基于[D-Ala24]GRP(20-26)-七肽的bombesin/胃泌素释放肽拮抗剂。修改导致有效的类似物与延长的作用时间。

Drug design and delivery Pub Date : 1990-10-01
J R Best, R Cotton, A S Dutta, B Fleming, A Garner, J J Gormley, C F Hayward, P F McLachlan, P B Scholes
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引用次数: 0

摘要

基于[D-Ala24]GRP的20-26七肽序列His-Trp-Ala-Val-D-Ala-His-Leu的胃泌素释放肽(GRP)和bombesin的类似物已经合成,并在体外测试了它们抑制GRP(18-27)诱导的瑞士3T3细胞有丝分裂的能力。在该测试系统中被鉴定为强效拮抗剂的化合物也在体内测试了它们抑制炸弹素诱导的大鼠淀粉酶分泌的能力。发现Trp-Ala-Val序列是拮抗活性的一个重要特征;在这一区域的大多数替换要么导致效力低得多或无活性的类似物。相比之下,分子其他部分的氨基酸替换更耐受性,有时会导致体外和体内活性的显着增加。用MeLeu代替Leu26,用Lys(X) (X = Z)、PhCO、PhCH2CO或Ph(CH2)2CO代替His25,得到了最有效的类似物。因此,4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)- leu - NHMe(86)和4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)- meleu - ome(87)的体内IC50值小于20 μ g /kg s.c.,其作用持续时间超过3小时。
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Antagonists of bombesin/gastrin releasing peptide based on [D-Ala24]GRP(20-26)-heptapeptide. Modifications leading to potent analogues with prolonged duration of action.

Analogues of gastrin releasing peptide (GRP) and bombesin based on His-Trp-Ala-Val-D-Ala-His-Leu, the 20-26 heptapeptide sequence of [D-Ala24]GRP, have been synthesized and tested in vitro for their ability to inhibit GRP (18-27)-induced mitogenesis in Swiss 3T3 cells. Compounds identified as potent antagonists in this test system were also tested in vivo for their ability to inhibit bombesin-induced amylase secretion in rats. The Trp-Ala-Val sequence was found to be a very important feature of the antagonist activity; most substitutions in this region led either to much less potent or inactive analogues. In contrast, amino acid replacements in other parts of the molecule were more tolerated and sometimes led to marked increases in the in vitro and in vivo activity. The most potent analogues were obtained by replacing Leu26 by MeLeu and His25 by Lys(X) where X = Z, PhCO, PhCH2CO or Ph(CH2)2CO. Thus 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)-Leu- NHMe (86) and 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)-MeLeu-OMe (87) had IC50 values of less than 20 micrograms/kg s.c. in vivo, and their effects lasted for more than 3 hr.

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