Hocart S J, Nekola M V, Coy D H
J Med Chem. 1985 Jul;28(7):967-70. doi: 10.1021/jm00145a022.
The structure-activity relationship of position 7 in the antagonist [N-Ac-D-Nal1,D-pClPhe2,D-Trp3,D-Arg6,D-Ala10]-LH-RH has been investigated by the incorporation of a series of amino acids at this position. The analogues were prepared by solid-phase peptide synthesis. All purifications were performed in two stages: gel permeation followed by preparative reversed-phase high-performance liquid chromatography. The analogues were assayed in the standard rat antiovulatory assay using a 40% propylene glycol-saline vehicle. The results demonstrated that position 7 requires a hydrophobic aromatic amino acid for greatest antiovulatory activity. The compound [N-Ac-D-Nal1,D-pClPhe2,D-Trp3,D-Arg6,Phe7,D-Ala10]-LH- RH caused 65% blockade of ovulation at the 500-ng dose and is approximately twice as active as the parent analogue in this assay system. The enhanced activity may indicate the stabilization of the active conformation via intramolecular hydrophobic or tau-tau interactions.
通过在拮抗剂[N - 乙酰 - D - 萘丙氨酸1，D - 对氯苯丙氨酸2，D - 色氨酸3，D - 精氨酸6，D - 丙氨酸10] - LH - RH的第7位引入一系列氨基酸，研究了该位置的构效关系。类似物通过固相肽合成制备。所有纯化均分两个阶段进行：凝胶渗透，然后是制备型反相高效液相色谱。使用40%丙二醇 - 盐水载体在标准大鼠抗排卵试验中对类似物进行测定。结果表明，第7位需要一个疏水性芳香族氨基酸以获得最大的抗排卵活性。化合物[N - 乙酰 - D - 萘丙氨酸1，D - 对氯苯丙氨酸2，D - 色氨酸3，D - 精氨酸6，苯丙氨酸7，D - 丙氨酸10] - LH - RH在500 ng剂量时引起65%的排卵阻断，在该试验系统中活性约为母体类似物的两倍。活性增强可能表明通过分子内疏水或τ-τ相互作用使活性构象稳定。
