Rivier J, Kupryszewski G, Varga J, Porter J, Rivier C, Perrin M, Hagler A, Struthers S, Corrigan A, Vale W
The Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037.
J Med Chem. 1988 Mar;31(3):677-82. doi: 10.1021/jm00398a030.
In order to improve the biological potency of cyclic gonadotropin releasing hormone (GnRH) antagonists, we have synthesized analogues, the conformations of which were restrained through internal side chain/side chain amide bridges linking aspartic acid or glutamic acid and L-2,3-diaminopropionic acid or L-ornithine. A disulfide bridge linking L-cysteine residues was also introduced. Residues belonging to the bridge spanned from position 4 to positions 9 or 10. Two series of analogues were synthesized and are characterized by residues at positions 1 [Ac-D-3-(2'-naphthyl)alanine], 2 [D-(4-chlorophenyl)alanine or D-(4-fluorophenyl)alanine], 3 [D-3-(3'-pyridyl)alanine or D-tryptophan], 5 (arginine or tyrosine), and 6 [D-3-(3'-pyridyl)alanine or D-arginine], respectively. These substitutions were selected in an effort to optimize high biopotency for inhibition of luteinizing hormone secretion, minimization of histamine release activity, and high (relative) hydrophilicity. The most potent analogues in the antiovulatory assay were cyclo(4-10) [Ac-DNal1,DCpa2,DPal3,(Asp4 or Glu4),Arg5,DPal]6,Dpr10]GnRH (compounds 5 and 7), which were fully active at ca. 12.5 micrograms/rat in the first series, and cyclo(4-10)[Ac-DNal1,DFpa2,DTrp3,Asp4,DArg6++ +,Dpr10]GnRH (compound 12), which was fully active at 2.5 micrograms/rat in the second.
为提高环促性腺激素释放激素（GnRH）拮抗剂的生物学活性，我们合成了类似物，其构象通过连接天冬氨酸或谷氨酸与L-2,3-二氨基丙酸或L-鸟氨酸的内部侧链/侧链酰胺桥来限制。还引入了连接L-半胱氨酸残基的二硫键。属于该桥的残基跨度从第4位到第9或第10位。合成了两个系列的类似物，其特征分别在于第1位[Ac-D-3-(2'-萘基)丙氨酸]、第2位[D-(4-氯苯基)丙氨酸或D-(4-氟苯基)丙氨酸]、第3位[D-3-(3'-吡啶基)丙氨酸或D-色氨酸]、第5位（精氨酸或酪氨酸）和第6位[D-3-(3'-吡啶基)丙氨酸或D-精氨酸]的残基。选择这些取代是为了优化抑制促黄体生成素分泌的高生物学活性、组胺释放活性的最小化以及高（相对）亲水性。抗排卵试验中最有效的类似物是环(4-10)[Ac-DNal1,DCpa2,DPal3,(Asp4或Glu4),Arg5,DPal]6,Dpr10]GnRH（化合物5和7），在第一个系列中，其在约12.5微克/大鼠时具有完全活性；以及环(4-10)[Ac-DNal1,DFpa2,DTrp3,Asp4,DArg6++ +,Dpr10]GnRH（化合物12），在第二个系列中，其在2.5微克/大鼠时具有完全活性。
