Effect of reductive alkylation of D-lysine in position 6 on the histamine-releasing activity of luteinizing hormone-releasing hormone antagonists.
Effect of reductive alkylation of D-lysine in position 6 on the histamine-releasing activity of luteinizing hormone-releasing hormone antagonists.
复制标题
6 位 D-赖氨酸还原烷基化对黄体生成素释放激素拮抗剂组胺释放活性的影响。
DOI：
10.1021/jm00387a030
复制
发表时间：
1987
影响因子：
7.3
通讯作者：
Coy,DH
中科院分区：
文献类型：
--
作者：
Hocart,SJ;Nekola,MV;Coy,DH
The reductive alkylation of the o-Lys side chain in position 6 of the LH-RH antagonist [JV-Ac-D-NaP. D-Phe2, 3^-Arg6, Phe7, D-Ala10] LH-RH was investigated in an attempt to reduce the histamine-releasing activity inherentto most potent antagonists while retaining high antiovulatory activity. The protected parent analogue was prepared by conventional solid-phase peptide synthesis. After selective removal of the Lys Fmoc side-chain protection, the resin-bound peptide was readily and conveniently alkylated at the e amino group with various aldehydes and ketones in the presence of NaCNBH3. The analogues were then cleaved from the resin with simultaneous deprotection by anhydrous hydrogen fluoride and purified to homogeneity in two stages: gel permeation followed by preparative reversed-phase liquid chromatography. The analogues were assayed in standard rat antiovulatory and in vitro histamine-release assays. Simple alkyl groups such as ethyl, isopropyl, neopentyl, and cyclohexyl caused little reduction in histamine-releasing activity while exhibiting antiovulatory activity similar to that of the parent peptide. The presence of benzyland substituted benzylgroups resulted in substantial losses of both histamine-releasingand antiovulatory activities. Thus, results showed that alterations in the hydrophobicity and size of the position-6 side chain have little effect on histamine-releasing activity or antiovulatory activity as long as a high degree of basicity is retained.Since theelucidation of the structure of the luteinizing hormone-releasing hormone (LH-RH) Glp-His-Trp-Ser-Tyr-Gly-Arg-Leu-Pro-Gly-NH2 by Matsuo et al. 2 in 1971, many hundreds of analogues have been synthesized in the search for ever more potent agonists and antagonists. The
