Seprodi J, Coy D H, Vilchez-Martinez J A, Pedroza E, Schally A V
J Med Chem. 1978 Mar;21(3):276-80. doi: 10.1021/jm00201a008.
Benzoyl-, acetylsalicylyl-, indomethacinyl-, pyroglutamylhistidyl-, and pyroglutamyl-D-phenylalanyl-D-tryptophanylseryltyrosyl groups were attached to a moderately active inhibitory analogue of LH-RH, [D-Phe2,D-Trp3-D-Lys6]-LH-RH, via the epsilon-amino group of the lysine residue. The resulting compounds were assayed for anti-LH-RH activity and for their ability to block ovulation in the rat. The decrease in polarity and increase in size of the lysine side chain resulting from addition of the aromatic acyl groups gave almost no increase in inhibitory activity. Addition of the dipeptide, less than Glu-His, also had little effect on potency. However, incorporation of the pentapeptide sequence to give a branched pentadecapeptide with essentially two N termini resulted in antiovulatory activity greater than the parent peptide or any other analogue thus far tested by us. The corresponding agonist peptide, [Nepsilon-(less than Glu-His-Trp-Ser-Tyr)-D-Lys6]-LH-RH, was also synthesized and tested for LH- and FSH-releasing activity. Surprisingly, it was no more active than [D-Lys6]-LH-RH itself, suggesting that an intact C terminus as well as an N terminus is necessary for the full expression of gonadotropin release.
苯甲酰基、乙酰水杨酸基、吲哚美辛基、焦谷氨酰组氨酰基以及焦谷氨酰-D-苯丙氨酰-D-色氨酰丝氨酰酪氨酰基通过赖氨酸残基的ε-氨基连接到促黄体生成素释放激素（LH-RH）的一个中等活性抑制类似物[D-苯丙氨酸²，D-色氨酸³，D-赖氨酸⁶]-LH-RH上。对所得化合物进行抗LH-RH活性及阻断大鼠排卵能力的测定。由于添加芳香酰基导致赖氨酸侧链极性降低和尺寸增大，抑制活性几乎没有增加。添加小于谷氨酸-组氨酸的二肽对效力也几乎没有影响。然而，并入五肽序列以形成具有两个N端的分支十五肽，其抗排卵活性大于母体肽或我们迄今测试的任何其他类似物。还合成了相应的激动剂肽[Nε-(小于谷氨酸-组氨酸-色氨酸-丝氨酸-酪氨酸)-D-赖氨酸⁶]-LH-RH，并对其促黄体生成素（LH）和促卵泡生成素（FSH）释放活性进行了测试。令人惊讶的是，它的活性并不比[D-赖氨酸⁶]-LH-RH本身更高，这表明完整的C端以及N端对于促性腺激素释放的充分表达是必要的。
