Effect of the CH2NH and CH2NAc peptide bond isosteres on the antagonistic and histamine releasing activities of a luteinizing hormone-releasing hormone analogue.
Effect of the CH2NH and CH2NAc peptide bond isosteres on the antagonistic and histamine releasing activities of a luteinizing hormone-releasing hormone analogue.
复制标题
CH2NH 和 CH2NAc 肽键电子等排体对黄体生成素释放激素类似物的拮抗和组胺释放活性的影响。
DOI：
10.1021/jm00117a024
复制
发表时间：
1988
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 effect of the CH2NH and CH2NAc peptide bond isosteres on the antagonistic and histamine releasing activities of the LH-RH antagonist [N-Ac-D-Nal1, D-Phe2’3, D-Arg6, Phe7, D-Ala10] LH-RH was investigated. The moieties were introduced by facile, racemization-free solid-phase synthesis in an attempt to reduce the histamine releasing activity inherent to the most potent analogues while retaining high antiovulatory activity. The/2] isostere was incorporated at each CONH site with the exception of 8-9, which involves Pro, by reductive alkylation with a protected amino acid aldehyde in the presence of NaBH3CN during conventional solid-phase peptide synthesis. The i/-[CH2NH] group was extremely resistant to derivatization and could only be partially acetylated to give i/[CH2NAc]. The analogues were 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. The isosterescaused a loss of the antiovulatory activity of the antagonist at the 50-µ § dose whenincorporated at the positions 1-2, 2-3, 3-4, and 7-8. Incorporation at the other positions resulted in a less marked reduction inactivity relative to the unmodified parent analogue. No significant effect was noted on the potent histamine releasing activity of theanalogues.
