Ljungqvist A, Feng D M, Hook W, Shen Z X, Bowers C, Folkers K
Institute for Biomedical Research, University of Texas, Austin 78712.
Proc Natl Acad Sci U S A. 1988 Nov;85(21):8236-40. doi: 10.1073/pnas.85.21.8236.
Antide is the decapeptide N-Ac-D-Nal(2),D-Phe(pCl),D-Pal(3),Ser,Lys(Nic),D-Lys(Nic),Leu,Lys(iPr),P ro,D- Ala-NH2 [Nal(2) represents 3-(2-naphthyl)alanine; Phe(p-Cl) represents 3-(4-chlorophenyl)alanine; Pal(3) represents 3-(3-pyridyl)alanine; Lys(Nic) represents N epsilon-nicotinoyllysine; Lys-(iPr) represents N epsilon-isopropyllysine], which is an antagonist of luteinizing hormone-releasing hormone (LHRH), which has high antiovulatory activity, releases negligible histamine, and is scheduled for scale-up, safety testing, and evaluation in the experimental primate and in clinical medicine. Thirty-five more peptides were synthesized, designed on antide with variations in positions 5-8. Of these, N-Ac-D-Nal(2),D-Phe(pCl),D-Pal(3),Ser,Lys(Pic),cis-D- Ala(PzAC),Leu,Lys(iPr),Pro,D-Ala-NH2 [Lys(Pic) represents N epsilon-picoloyllysine; Ala(PzAC) represents 3-(4-pyrazinylcarbonylaminocyclohexyl)alanine] was not only the most potent but also had higher antiovulatory activity than antide--i.e., 73% per 0.25 microgram and 100% per 0.5 microgram vs. 36% per 0.5 microgram and 100% per 1.0 microgram. Antide showed significant (P less than 0.001) duration of action when injected at a dose of 10 micrograms 44 hr before injection of 50 ng of the agonist [D-Qal(3)6]LHRH [Qal(3) represents 3-(3-quinolyl)alanine]. Antide showed oral antiovulatory activity at 600 micrograms (73%) and at 1200 micrograms (100%) with negligible difference between water and corn oil oral formulations.
安替肽是一种十肽，即N - 乙酰 - D - 萘丙氨酸(2)，D - 对氯苯丙氨酸，D - 3 - 吡啶基丙氨酸，丝氨酸，Nε - 烟酰赖氨酸，D - Nε - 烟酰赖氨酸，亮氨酸，Nε - 异丙基赖氨酸，脯氨酸，D - 丙氨酰胺[Nal(2)代表3 - (2 - 萘基)丙氨酸；Phe(p - Cl)代表3 - (4 - 氯苯基)丙氨酸；Pal(3)代表3 - (3 - 吡啶基)丙氨酸；Lys(Nic)代表Nε - 烟酰赖氨酸；Lys - (iPr)代表Nε - 异丙基赖氨酸]，它是促黄体生成素释放激素(LHRH)的拮抗剂，具有高抗排卵活性，释放的组胺可忽略不计，并且计划在实验灵长类动物和临床医学中进行放大生产、安全性测试和评估。在安替肽的基础上，在5 - 8位进行了变化，又合成了35种更多的肽。其中，N - 乙酰 - D - 萘丙氨酸(2)，D - 对氯苯丙氨酸，D - 3 - 吡啶基丙氨酸，丝氨酸，Nε - 甲基吡啶甲酰赖氨酸，顺式 - D - 3 - (4 - 吡嗪基甲酰氨基环己基)丙氨酸，亮氨酸，Nε - 异丙基赖氨酸，脯氨酸，D - 丙氨酰胺[Lys(Pic)代表Nε - 甲基吡啶甲酰赖氨酸；Ala(PzAC)代表3 - (4 - 吡嗪基甲酰氨基环己基)丙氨酸]不仅是最有效的，而且具有比安替肽更高的抗排卵活性，即每0.25微克为73%，每0.5微克为100%，而安替肽每0.5微克为36%，每1.0微克为100%。当在注射50纳克激动剂[D - Qal(3)6]LHRH[Qal(3)代表3 - (3 - 喹啉基)丙氨酸]前44小时以10微克的剂量注射时，安替肽显示出显著的(P小于0.001)作用持续时间。安替肽在600微克(73%)和1200微克(1×100%)时显示口服抗排卵活性，水和玉米油口服制剂之间的差异可忽略不计。
