Hocart S J, Nekola M V, Coy D H
J Med Chem. 1987 Apr;30(4):735-9. doi: 10.1021/jm00387a029.
The structure-activity relationship of the hydrophobic amino terminal region of the antagonist [N-Ac-D-Nal1,D-pClPhe2,D-Trp3,D-Arg6,Phe7,D-Ala10]-LH- RH has been investigated by the incorporation of a variety of amino acids with emphasis on positions 1, 2, and 3. The analogues were prepared by routine solid-phase peptide synthesis. All purifications were performed in two stages: gel permeation chromatography followed by preparative, reversed-phase, high-performance chromatography. The analogues were assayed in a standard rat antiovulatory assay using a 40% propane-1,2-diol-saline vehicle. A simplified antagonist was developed that allowed the removal of the custom-synthesized D-pClPhe and the labile D-Trp while retaining antiovulatory potency. The compound [N-Ac-D-Nal1,D-Phe2,3,D-Arg6,Phe7,D-Ala10]-LH-RH caused a 56% blockade of ovulation at the 500-ng dose and is approximately equipotent with the parent analogue in this system.
通过引入多种氨基酸，重点研究拮抗剂[N-乙酰基-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]-促性腺激素释放激素疏水氨基末端区域的构效关系，重点关注第1、2和3位。类似物通过常规固相肽合成制备。所有纯化均分两个阶段进行：凝胶渗透色谱，然后是制备型反相高效色谱。类似物在标准大鼠抗排卵试验中使用40%丙二醇-盐水载体进行测定。开发了一种简化的拮抗剂，可去除定制合成的D-对氯苯丙氨酸和不稳定的D-色氨酸，同时保留抗排卵效力。化合物[N-乙酰基-D-萘丙氨酸1，D-苯丙氨酸2，3，D-精氨酸6，苯丙氨酸7，D-丙氨酸10]-促性腺激素释放激素在500 ng剂量时引起56%的排卵阻断，在该系统中与母体类似物大致等效。
