Ljungqvist A, Feng D M, Tang P F, Kubota M, Okamoto T, Zhang Y W, Bowers C Y, Hook W A, Folkers K
Institute for Biomedical Research, University of Texas, Austin 78712.
Biochem Biophys Res Commun. 1987 Oct 29;148(2):849-56. doi: 10.1016/0006-291x(87)90953-3.
Potent antagonists of the luteinizing hormone releasing hormone have been achieved which release negligible histamine. [N-Ac-D-2-Nal1, D-pClPhe2, D-3-Pal3, NicLys5, D-NicLys6, ILys8, D-Ala10]-LHRH showed 100%AOA/1 microgram and 36%/0. 5 micrograms; ED50 greater than 300. [N-Ac-D-2-Nal1,D-pClPhe2,D-3-Pal3, PicLys5, D-PicLys6, ILys8, D-Ala10]-LHRH showed 100% AOA/0.5 micrograms and 40%/0.25 micrograms; ED50, 93 +/- 11, and is the most potent of 52 new peptides. These antagonists feature designs with weakly basic acylated D-Lys6, notably D-NicLys6 and D-PicLys6 and alkylated Lys8 or Orn8, e.g., ILys8 and IOrn8, and NicLys5 and PicLys5. Concepts included balanced overall basicity, superiority of ILys8 and IOrn8 which are sequence dependent and sensitivity of positions 5 and 6 for potency.
已获得促黄体生成激素释放激素的强效拮抗剂，其释放的组胺可忽略不计。[N-乙酰-D-2-萘丙氨酸1、D-对氯苯丙氨酸2、D-3-哌啶丙酸3、烟酰胺赖氨酸5、D-烟酰胺赖氨酸6、异亮氨酸8、D-丙氨酸10]-促黄体生成激素释放激素在1微克时显示100%的活性，在0.5微克时显示36%的活性；半数有效剂量大于300。[N-乙酰-D-2-萘丙氨酸1、D-对氯苯丙氨酸2、D-3-哌啶丙酸3、吡啶甲酰赖氨酸5、D-吡啶甲酰赖氨酸6、异亮氨酸8、D-丙氨酸10]-促黄体生成激素释放激素在0.5微克时显示100%的活性，在0.25微克时显示40%的活性；半数有效剂量为93±11，是52种新肽中活性最强的。这些拮抗剂的特点是设计有弱碱性酰化的D-赖氨酸6，特别是D-烟酰胺赖氨酸6和D-吡啶甲酰赖氨酸6，以及烷基化的赖氨酸8或鸟氨酸8，例如异亮氨酸8和异鸟氨酸8，还有烟酰胺赖氨酸5和吡啶甲酰赖氨酸5。其设计理念包括平衡的整体碱性、异亮氨酸8和异鸟氨酸8在序列依赖性方面的优势以及第5和第6位对活性的敏感性。
