Geometric Isomers of Substituted Triphenylethylenes and Antiestrogen Action

Abstract

The estrogenic and antiestrogenic activities of tamoxifen ICI 47,699, enclomiphene, zuclomiphene, and the geometric isomers of monohydroxytamoxifen and CI628 were determined in the 3-day immature rat uterine weight test. Tamoxifen, enclomiphene, and the releated geometric isomers of monohydroxytamoxifen and CI628 were partially estrogenic with antiestrogenic properties. ICI 47,699 and zuclomiphene were predominantly estrogenic; however, an antiestrogen effect for zuclomiphene (100 micrograms daily) was demonstrable and large doses of ICI 47,699 (1 or 10 mg daily) inhibited full estrogen action. In contrast, the geometric isomers of monohydroxytamoxifen and CI628 related to ICI 47,699 and zuclomiphene were partially estrogenic with antiestrogenic properties. The estrogenic properties of ICI 47,699 were classified in three ways: elevation of uterine wet weight, increase in whole uterine DNA, and increase in the mitotic activity of luminal epithelial cells. In general, ICI 47,699 was able to initiate estrogenic responses of DNA synthesis or mitosis by translocation of fewer cytoplasmic estrogen receptors to the nuclear compartment than tamoxifen. A model is proposed to explain antiestrogen action in terms of the geometric requirements for receptor binding. It is suggested that the position in space of the alkylaminoethoxyside chain is of fundamental importance. Overall, these data lend support to the view that a structurally specific ligand-estrogen receptor complex can influence the future events within a target tissue to produce either an agonist or an antagonist response.

Elimination of Antiestrogenic Effects of Active Tamoxifen Metabolites by Glucuronidation

“…Previous studies examining the antiestrogenic properties of TAM metabolite isomers have been hindered by the interconversion between the cis-and trans-isomers of TAM and TAM metabolites shown to occur in previous experimental systems (Jordan et al, 1981;Lieberman et al, 1983;Katzenellenbogen et al, 1984). The present study is the first to examine the antiestrogenic properties of relatively pure isomers of both 4-OH-TAM and endoxifen.…”

“…Interpretation of results from previous studies was difficult because of the possible interconversion between isomers. It was originally suggested that because cis-TAM is estrogenic, the antiestrogenic properties of cis-4-OH-TAM in a rat uterine weight test model may be due to interconversion to its trans-form (Jordan et al, 1981). A later study using a prolactin synthesis model demonstrated a stronger antiestrogenic effect for trans-4-OH-TAM compared with cis-4-OH-TAM and that neither isomer exhibited estrogenic properties, but these data were also confounded by the possibility of interconversion between isomers (Lieberman et al, 1983).…”

Structure-Activity Relationships of Estrogens

“…The principle is exemplified by the cis and trans geometric isomers of tamoxifen or clomiphene. Tamoxifen and enclomiphene (the trans isomers) are both paitial estrogen agonists in the immature rat with antiestrogenic properties (93)(94)(95). In contrast, the cis isomers, ICI 47,699 (Fig.…”

“…In contrast, the cis isomers, ICI 47,699 (Fig. 15) and zuclomiphene, are both estrogens (93)(94)(95). These types of observations have been used to develop models to describe estrogen and antiestrogen action in the rat (94,96).…”

“…15) and zuclomiphene, are both estrogens (93)(94)(95). These types of observations have been used to develop models to describe estrogen and antiestrogen action in the rat (94,96). The importance of a strategically located alkylaminoethoxy side chain for antagonist action has recently been illustrated (97) with derivatives of the estrogen cyclofenyl (Fig.…”