Juchem M, Pollow K, Elger W, Hoffmann G, Möbus V
Abteilung für Experimentelle Endokrinologie, Johannes Gutenberg-Universität Mainz, F.R.G.
Contraception. 1993 Mar;47(3):283-94. doi: 10.1016/0010-7824(93)90044-8.
Binding of the new progestagen, norgestimate (D-(-)-13 beta-ethyl-17 beta-acetoxy-17-ethinyl-4-gonen-3-one-oxime), and its metabolites (levonorgestrel-3-oxime, levonorgestrel-17-acetate and levonorgestrel) to the progesterone receptor was investigated by competition experiments using cytosol from human myometrial tissue. Compared to R5020, a highly potent synthetic ligand for progesterone receptor analysis, the L-isomer of norgestimate shows only a weak specific behaviour with regard to binding to the progesterone receptor from uterine cytosol with an RBA value of 0.8%, whereas the D-isomer of this compound is characterized by a lack of binding activity to the progesterone receptor. Levonorgestrel-3-oxime, one of the possible metabolites of norgestimate, binds to the progesterone receptor with an RBA value of 8%, whereas levonorgestrel-17-acetate, the other possible metabolite of norgestimate, binds with a binding affinity of 110% which is in the same order of magnitude as levonorgestrel itself. The competition experiments suggest that norgestimate is a prodrug and that the metabolites, levonorgestrel and levonorgestrel-17-acetate, which actively bind to the progesterone receptor, must first be formed from the parent drug via metabolic processes in vivo. These are the actual biologically active compounds which are responsible for the gestagenic potency.
采用人子宫肌层组织的胞质溶胶，通过竞争实验研究了新型孕激素诺孕酯（D-(-)-13β-乙基-17β-乙酰氧基-17-乙炔基-4-孕烯-3-酮肟）及其代谢产物（左炔诺孕酮-3-肟、左炔诺孕酮-17-乙酸酯和左炔诺孕酮）与孕酮受体的结合情况。与用于孕酮受体分析的高效合成配体R5020相比，诺孕酯的L-异构体在与子宫胞质溶胶中的孕酮受体结合方面仅表现出较弱的特异性行为，相对结合活性（RBA）值为0.8%，而该化合物的D-异构体则表现出对孕酮受体缺乏结合活性。诺孕酯的可能代谢产物之一左炔诺孕酮-3-肟与孕酮受体结合，RBA值为8%，而诺孕酯的另一种可能代谢产物左炔诺孕酮-17-乙酸酯的结合亲和力为110%，与左炔诺孕酮本身处于同一数量级。竞争实验表明，诺孕酯是一种前体药物，必须先通过体内代谢过程从母体药物形成能与孕酮受体有效结合的代谢产物左炔诺孕酮和左炔诺孕酮-17-乙酸酯。这些才是具有孕激素活性的实际生物活性化合物。
