Importance of the alkylaminoethoxy side-chain for the estrogenic and antiestrogenic actions of tamoxifen and trioxifene in the immature rat uterus

The estrogenic and antiestrogenic properties of tamoxifen and trioxifene were compared with their phenolic derivatives (ICI 77949 and LY 126412, respectively) without the alkylaminoethoxy side-chain. Trioxifene was a more potent antiestrogen than tamoxifen in immature rat uterine weight tests and both compounds were partial estrogen agonists. Removal of the side-chain from tamoxifen to produce ICI 77949 converted the compound from a partial estrogen agonist to a full estrogen agonist. Tamoxifen, trioxifene and ICI 77949, produced an estradiol-like increase in uterine progesterone receptor concentrations (as determined by sucrose density gradient analysis) and a dose-related, estradiol-like, increase in the size and shape of uterine luminal epithelial cells. In contrast, removal of the side-chain from trioxifene to produce LY 126412 converted the compound from a partial estrogen agonist, with antiestrogenic properties, to one with a very low affinity for the estrogen receptor and no biological activity in vivo at the daily doses tested (1-64 μg). This was established by uterine wet weight tests, histological examination of luminal epithelial cells and determination of progesterone receptor concentrations. The alkylaminoethoxy side-chain is not only necessary for the antiestrogenic properties of both tamoxifen and trioxifene but also essential for the effective estrogen receptor binding and pharmacological actions of trioxifene.