The influence of structural modification on progesterone and androgen receptor binding of norethisterone. Correlation with nuclear magnetic resonance signals

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Abstract
The relative binding affinities (RBA) of eight progestogens structurally derived from 17α-ethinyl-19-nortestosterone (norethisterone) have been estimated a) for the progesterone receptor from human premenopausal endometrium and b) for the androgen receptor in human mammary carcinoma in vitro. Introduction of a methylene group at C-11, a methyl group at C-18, or a double bond between C-15 and C-16 of the norethisterone molecule increases the RBA to the progesterone receptor. As a rough approximation, the substituent effects seem to be additive. RBA to the androgen receptor follows a more complex pattern when norethisterone is structurally modified. An additional methyl at C-18 enhances affinity to the androgen receptor. The double bond between C-15 and C-16 has no effect except when introduced into desogestrel, where it reduces RBA to the lowest value in the study. The methylene group at C-11 increases androgen RBA when present as the only substituent, but reduces androgen RBA when together with any other substituent. The complete assignment of 13C-NMR signals has been achieved for all 8 steroids investigated. The 13C-resonance signal of C-17 shows a correlation with the RBA to the progesterone receptor, and with the progestogen/androgen RBA ratios.

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