Rivier J, Theobald P, Porter J, Perrin M, Gunnet J, Hahn D W, Rivier C
Salk Institute for Biological Studies, La Jolla, California 92037.
Biochem Biophys Res Commun. 1991 Apr 15;176(1):406-12. doi: 10.1016/0006-291x(91)90939-5.
A series of GnRH antagonists with substitutions at positions 1, 2, 3, 5 and 6 that included the recently reported homoArg-N omega-cyano-N omega'-alkyl- or Lysine-N epsilon-5'-(3-amino-1H-1,2,4-triazole) [Lys(atz)] amino acid derivatives was synthesized, characterized and tested for antiovulatory and anaphylactoid activities and binding affinity. Overall, these analogs were found to be considerably more soluble at neutral pH than their homologs Nal-Glu or Antide. The decapeptides with these substitutions in positions 5 and/or 6 retained high in vivo potency while those with similar substitutions at positions 1, 2 and 3 were significantly less potent than Nal-Glu or Antide. Of the 16 new analogs reported here, Azaline (Ac-DNal1, DCpa2, DPal3, Lys5(atz),DLys6(atz), ILys8,DA1a10]-GnRH) showed the most promising physico-chemical and biological properties [Lys(atz) = N epsilon-5'-(3-amino-1H-1,2,4-triazole) lysine]. Azaline is readily soluble in dilute buffers at pH 7.0, completely inhibits ovulation at 2.0 to 3.0 micrograms per rat, is equipotent to GnRH in releasing histamine in the rat and has a weaker anaphylactoid response in the rat than other analogs such as Nal-Glu or even Antide.
合成了一系列在第1、2、3、5和6位有取代基的促性腺激素释放激素（GnRH）拮抗剂，其中包括最近报道的高精氨酸-Nω-氰基-Nω'-烷基-或赖氨酸-Nε-5'-(3-氨基-1H-1,2,4-三唑)[Lys(atz)]氨基酸衍生物，并对其进行了表征，测试了其抗排卵、类过敏活性及结合亲和力。总体而言，发现这些类似物在中性pH下的溶解度比其同系物Nal-Glu或Antide高得多。在第5和/或6位有这些取代基的十肽保留了较高的体内活性，而在第1、2和3位有类似取代基的十肽的活性明显低于Nal-Glu或Antide。在本文报道的16种新类似物中，Azaline（Ac-DNal1, DCpa2, DPal3, Lys5(atz),DLys6(atz), ILys8,DA1a10]-GnRH）表现出最有前景的物理化学和生物学特性[Lys(atz)=Nε-5'-(3-氨基-1H-1,2,4-三唑)赖氨酸]。Azaline在pH 7.0的稀缓冲液中易溶，以每只大鼠2.0至3.0微克的剂量可完全抑制排卵，在大鼠体内释放组胺方面与GnRH等效，并且在大鼠体内的类过敏反应比其他类似物如Nal-Glu甚至Antide弱。
