Inhibition of oestradiol binding to mouse uterine and vaginal oestrogen receptors by triphenylethylenes

Harper and Walpole (1967) reported the potent antioestrogenic activity of ICI 46,474, the trans isomer of 1 (p β dimethylaminoethoxyphenyl) 1,2 diphenylbut 1 ene, in the rat; howerver, in the mouse the compound exhibited only oestrogenic properties. However, Emmens (1971) showed that large doses of ICI 46,474 or the related compound H774 (1 (p β diethylaminoethoxyphenyl) 1,2 di(p methoxyphenyl) but 1 ene citrate) caused vaginal refractoriness to oestradiol for several weeks after s.c. administration to ovariectomized mice. The present study was undertaken to determine the ability of ICI 46,474 and H774 to inhibit binding of [³H] oestradiol to the 8S oestrogen receptor derived from ovariectomized mouse uterus and vagina. The results demonstrate the presence of an 8 S oestradiol binding macromolecule in both the mouse uterus and vagina. Since ICI 46,474 and H774 inhibit the binding of oestradiol to the mouse uterine and vaginal oestrogen receptors, then part of their mechanism of action as antioestrogens and antifertility agents may be explained by direct antagonism of the first step of oestrogen action at target tissues, i.e. binding to the oestrogen receptor. The interaction with the oestrogen receptor also suggests how these compounds initiate oestrogenic responses.