STRUCTURE-ACTIVITY RELATIONSHIPS OF ANTI-OESTROGENS WITH REGARD TO INTERACTION WITH 17β-OESTRADIOL IN THE MOUSE UTERUS AND VAGINA

Anti-oestrogenic substances have been studied systematically in order to get some guides about structure - activity relationships. The substances were tested in the mouse a) for uterotrophic and anti-uterotrophic activities and b) for their capacity to inhibit the uptake of 17β-oestradiol by the uterus and vagina in vitro. A few such in vitro experiments were also carried out in the rat.

Only MER-25 was completely devoid of any oestrogenic activity and was able to suppress oestrogenic stimulation completely. U-11,100A and CN-55,945 were partial agonists producing less than total oestrogen antagonism. MRL-37, DMS, meso-butoestrol, oestriol and ent-17β-oestradiol were impeded oestrogens, i. e., produced dose-response curves with shallow slopes. These compounds, except oestriol which was inactive, were weakly anti-uterotrophic. Cis- and trans-clomiphene, ICI-47,699 and ICI-46,474 which are also cis/trans isomers, WSM-4613 and U-11,555A showed no sign of anti-oestrogenic activity.

All the tested substances suppressed the binding of 17β-oestradiol to the mouse uterus and vagina. The impeded oestrogens were generally very potent. However, their inhibitory action was of short duration since they were easily washed out. The remaining compounds (dialkylamino-alkyl-ether derivatives) were generally very firmly bound to the target tissues, the binding being even firmer than that of the oestrogens 17β-oestradiol or meso-hexoestrol.

Possible mechanisms of actions of the two kinds of anti-oestrogens are presented. A model explaining the impeded uterotrophic response is also given.