The binding of [3H]progesterone and [3H] 16 alpha,17 alpha-cycloalkanoprogesterones to proteins from rat, rabbit, and human uteri and other organs was studied. We found that 16 alpha,17 alpha-cycloalkanoprogesterone derivatives display affinities for the uterine progesterone receptors comparable with that of the natural hormone and no substantial species differences in the affinity. Rabbit uterus was found to have no proteins distinct from the progesterone receptor that specifically bind [3H] 16 alpha,17 alpha-cycloalkanoprogesterones. At the same time, in the human uterus, we found another protein that binds some of these progesterone derivatives; it turned out to be similar to the protein from rat uterus. A similar protein with the same selectivity and affinity for steroids was also found in rat and human kidneys. Blood serum, liver, lung, and a number of other tissues were found to contain a protein of the third type that binds the same 16 alpha,17 alpha-cycloalkanoprogesterones and exhibits submicromolar Kd values for these steroids and a very low affinity for progesterone. We speculated that the introduction of a bulky substituent adjacently to the 17 beta-side chain of progesterone could result in a change in the general biodynamics of the derivative including its transport, uptake, and accumulation in tissues, which may determine the selectivity of its effect.
The synthesis, modification, structure, and biological activity in vivo of the 16 α ,17 α -cycloalkanoprogesterone (pregna-D'-pentarane) analogues of progesterone are described. A possibility of separation of their biological functions has been demonstrated. A systematic synthesis of a set of uniform compounds that differ in a limited number of alterable parameters was developed. It resulted in an instrument useful for the investigation of pathways and mechanisms by which the steroid hormones fulfill their biological functions and for the probable discovery of new functions masked by the wide effects of native compounds.
Antiprogestin activity of 5H-progesterone metabolites and their analogues 16alpha,17alpha-cyclohexan-5H-pregnan-3,20-diones was tested on rats. Modified pregnancy interruption test showed that 5alpha (H)-isomers of natural and synthetic hormones exhibit maximum activity.
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