Structure-activity relationships of estrogens.

Abstract

The last 50 years has seen an exponential rise in the published reports about estrogen action. The model to describe the early events in the mechanism of action of estrogens via the estrogen receptor is updated in this paper to incorporate some of the recent data on the subcellular localization of the receptor. New evidence suggests that the receptor is a nuclear protein, so it appears that estrogens must first diffuse into the nuclear compartment to initiate estrogen action via the receptor complex. This review traces the development of potent estrogenic compounds by the study of their structure-activity relationships. Studies of structure-activity relationships in vivo using Allen Doisy or 3-day uterine weight tests can provide much valuable information, but the assays suffer from the complex problems of pharmacokinetics and metabolic transformation. Studies in vitro using primary cultures of rat pituitary or uterine cells to assay the ability of a compound to induce prolactin synthesis or progesterone receptor synthesis, respectively, can provide essential information about the structural requirements for a compound to produce estrogenic effects. Nevertheless, it should be pointed out that studies in vivo are required to determine whether a compound is metabolically activated to an estrogen. Estrogen receptor binding models are presented to describe the changes in a molecule that will predict high affinity for the ligand and agonist, partial agonist and antagonist properties of the ligand-receptor complex. Most estrogenic pesticides and phytoestrogens comform to the predictions of the estrogen receptor binding model.

The influence of equol on the hypothalamic–pituitary–thyroid axis and hepatic lipid metabolic parameters in adult male rats

“…Equol has the molecular structure similar to 17β-estradiol [12,36] that potently binds to both estrogen receptor subtypes beta (ERβ) and alpha (ERα), and exerts more estrogenic actions than the parent compound [21,25,34]. In addition to its well-characterized estrogenic actions, there is increasing evidence that equol has potential as an androgen receptor (AR) antagonist because in vitro it has been demonstrated to bind with high affinity to AR [5], and inhibit proliferation of benign and malignant human prostatic cells and cell lines [10], prostate growth and in vivo feedback effects of 5α-dihydrotestosterone [21,22], which till date has attracted intensive interests from many physicians and offers insights into prevention of androgen-dependent prostate disorders [10,21,22].…”

Suppression of liver Apo E secretion leads to HDL/cholesterol immaturity in rats administered ethinylestradiol

“…Ethinylestradiol possesses extremely potent estrogen activity similar to DES 24. The exposure to EE at only a single dose suppressed Apo E secretion from the liver, leading to a decrease in HDL cholesterol as shown Figs 3, 4 and 6.…”

Predicting pharmacophore signals for post-coital antifertility activity of 1-trifluoromethyl-1,2,2-triphenylethylene derivatives: a statistical approximation using E-state index

“…11,35 From the regression analysis it appears that C3, C5 and F22 atoms of the molecule constitute the most significant role for post-coital antifertility activity. Importance of the phenyl ring fragment attached to the 2nd ethylenic carbon can thus be envisaged.…”

“…Importance of the phenyl ring fragment attached to the 2nd ethylenic carbon can thus be envisaged. 11,35 Saturation of the ethylenic double bond (Compound 18) causes increase of S-value at C3 atom that resulted in marked decrease of activity 17 and in fact exhibited the least activity among the set of 18 molecules. Hence, not only the phenyl ring but also that being attached to an ethylenic carbon seems to be crucial.…”

“…From Figure 1, it can be observed that C3 is the point of attachment of the phenyl ring to an ethylenic carbon, which has been demonstrated to be one of the principal contributor for activity. Substitution by hydroxyl group 35 and alkyl ether analogue 2 at C6 or C12 of non-steroidal estrogen analogues increases affinity for the receptor. Substitution by a p-CH 3 O group (e À donating) in the phenyl ring causing an increase of e À density around adjacent atoms of the ring (particularly at C5, C7, C11 or C13 which have negative contribution) resulted in marked increase of activity.…”