Ligand interaction at the estrogen receptor to program antiestrogen action: a study with nonsteroidal compounds in vitro.

The estrogenic and antiestrogenic actions of the geometric isomers of tamoxifen and 4-hydroxytamoxifen were determined in a PRL synthesis assay using primary cultures of dispersed immature rat pituitary gland cells. 4-Hydroxytamoxifen was 100 times more potent as an antiestrogen than tamoxifen. The cis isomer of tamoxifen was a weak estrogen, but the cis isomer of 4-hydroxytamoxifen was converted to the trans isomer during the 6-day assay. This made an accurate determination of the properties of cis-(E)4-hydroxytamoxifen impossible. A series of fixed ring derivatives of the compounds were evaluated in the PRL synthesis assay in vitro to determine their estrogenic and antiestrogenic activities. The fixed ring derivatives of tamoxifen, cis-tamoxifen and trans-(Z)4-hydroxytamoxifen all had properties that were the same as those of the original triphenylethylenes. The fixed ring derivative of the cis-(E) isomer of 4-hydroxytamoxifen was a weak competitive antagonist of estrogen action with only very slight estrogenic properties. This contrasted with the other cis isomers of triphenylethylenes. We propose that the hydroxyl group on the molecule may orient the ligand at the binding site of the estrogen receptor to place the alkylaminoethoxy side-chain in a position to produce antiestrogen action.