Receptor binding of norgestimate--a new orally active synthetic progestational compound

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.