Antiuterotrophic Activity Research Articles

Design, synthesis, estrogenic and antiestrogenic activities of some triarylpyrazole derivatives

New triarylpyrazole derivatives, substituted with basic side chain, polar group or heterocyclic ring were designed and synthesized. Nineteen compounds were tested for their in vivo uterotrophic activity. Animals treated with compounds 9, 15a, 15c, 19a, 19f, 20a, and 21b showed pronounced increase in uterine weight. It is worth mentioning that compound 19f was more active than estradiol as an estrogenic compound as evidenced by the increased dry uterine weight. Additionally, compound 19a produced 128.25% increase in dry uterine weight relative to estradiol. On the other hand, eight compounds were screened for their in vivo antiuterotrophic activity. Animals treated with compounds 5e, 5f, 8, and 13b showed pronounced decrease in uterine weight. The highest antiuterotrophic effect was observed in mice receiving compound 13b, which was as potent as the positive control, tamoxifen as evident by the decrease in the uterine wet weight.

Synthesis of some new diaryl and triaryl hydrazone derivatives as possible estrogen receptor modulators.

1,2-Bis(4-substituted phenyl)-2-methyl ethanone (2,4-dinitrophenyl)hydrazones and 1-naphthyl-1-(4-substituted phenyl)-methanone (2,4-dinitrophenyl)hydrazones have been synthesized and evaluated for their anti-implantation, uterotrophic, antiuterotrophic, anticancer and antimicrobial activities. Diphenolic hydrazone (compound 6) showed maximum uterotrophic inhibition of 70%, whereas compound 20 exhibited cytotoxicity in the range of 50-70% against MCF-7 and ZR-75-1 human malignant breast cell lines.

Effects of tamoxifen and ethynylestradiol cotreatment on uterine gene expression in immature, ovariectomized mice

Tamoxifen (TAM), the primary treatment for estrogen receptor (ER)-positive breast cancer, has been associated with an increased incidence of endometrial cancer in postmenopausal, but not premenopausal women. TAM elicits a partial ER-mediated uterotrophic response in immature rodents when compared with ethynylestradiol (EE), a potent ER agonist. However, cotreatment with 1000 microg/kg TAM antagonizes the uterotrophic effect induced by 30 microg/kg EE. To further investigate the anti-uterotrophic activity of TAM, immature, ovariectomized C57BL/6 mice were treated with a single oral dose of EE, TAM, EE+TAM, or vehicle, and harvested at 2, 4, 8, 12, 18, and 24 h or after three daily treatments at 72 h. Significant increases in uterine wet weight (UWW) were observed at 18 h for EE, TAM, and the mixture. However, mixture induction of UWW was significantly lower when compared with EE-induced uterotrophy at 72 h. This inhibitory effect is also reflected in decreases in luminal circumference, yet EE-induced luminal epithelial cell height was unaffected by cotreatment with TAM. Gene expression analysis using a 2 x 2 factorial cDNA microarray study design identified 2518 differentially expressed genes following EE treatment alone. However, only 290 EE-elicited gene expression changes were affected by TAM cotreatment, in a manner consistent with the anti-estrogenic response. These data suggest that TAM antagonism of EE-induced UWW increase involves the selective inhibition of EE-induced genes.

Evidence that 17alpha-estradiol is biologically active in the uterine tissue: Antiuterotonic and antiuterotrophic action

Background17alpha-Estradiol has been considered as the hormonally inactive isomer of 17beta-estradiol. Recently, nongenomic (smooth muscle relaxation) and genomic (light estrogenic activity) effects of 17alpha-estradiol have been reported, but no reports have yet determined its possible antiestrogenic activity. Therefore, this study investigated: the nongenomic action of 17alpha-estradiol on uterine contractile activity and its potential agonist-antagonist activity on uterine growth.MethodsUterine rings from rats were isometrically recorded. Different concentrations (0.2–200 microM) of 17alpha-estradiol were tested on spontaneous contraction and equimolarly compared with 17beta-estradiol. To examine the mechanism of 17alpha-estradiol action, its effect was studied in presence of beta2-antagonist (propranolol), antiestrogens (tamoxifen and ICI 182,780) or inhibitors of protein synthesis (cycloheximide) and transcription (actinomycin D). Moreover, contractions induced by high potassium (KCl) solution or calcium in depolarized tissues by KCl-calcium free solution were exposed to 17alpha-estradiol. Collaterally, we performed an uterotrophic assay in adult ovariectomized rats measuring the uterine wet weight. The administration for three days of 0.3 microM/day/Kg 17beta-estradiol was equimolarly compared with the response produced by 17alpha-estradiol. Antiuterotrophic activity was assayed by administration of 0.3 microM/day/Kg 17beta-estradiol and various doses ratios (1:1, 1:3, 1:5, and 1:100) of 17alpha-estradiol.ResultsThe estradiol isomers elicited an immediate relaxation, concentration-dependent and reversible on spontaneous contraction. 17alpha-Estradiol presented lower potency than 17beta-estradiol although it did not antagonize 17beta-estradiol-induced relaxation. Relaxation to 17alpha-estradiol was not inhibited by propranolol, tamoxifen, ICI 182,780, cycloheximide or actinomycin D. The KCl contractions were also sensitive to 17alpha-estradiol-induced relaxation and calcium contractions in depolarized tissues were markedly prevented by 17alpha-estradiol, implying a reduction of extracellular calcium influx through voltage-operated calcium channels (VOCCs). Uterotrophic assay detected significant increase in uterine weight using 17alpha-estradiol, which was significantly minor as compared with 17beta-estradiol. 17alpha-Estradiol, at all doses ratios, significantly antagonized the hypertrophic response of 17beta-estradiol.Conclusion17alpha-Estradiol induces a relaxing effect, which may be independent of the classical estrogen receptor, nongenomic action, apparently mediated by inactivation of VOCCs. 17alpha-Estradiol is also a weak estrogen agonist (uterotrophic response); likewise, 17alpha-estradiol may act as an antiestrogen (antiuterotrophic response). The overall data document a nongenomic relaxing action and a novel antiestrogenic action of 17alpha-estradiol, which are relevant in estrogen-mediated uterine physiology.

Synthesis and structure–activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution

EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA=380, IC50value=0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively.

Synthesis and biological activities of some new dibenzopyranones and dibenzopyrans: search for potential oestrogen receptor agonists and antagonists

Continuing our search for newer oestrogen agonists or antagonists and extending our work on the exploration of benzopyran related compounds, some new tricyclic molecules bridged between the active molecules of 3,4-diaryl chroman and 2,3-diaryl benzopyrans have been synthesised. Structural modifications at different positions with elements known to impart agonist or antagonist activities have been carried out to prepare the desired molecules. The target compounds were screened for their anti-osteoporotic (agonist) and anti-uterotrophic (antagonist) activities and were found to be moderately active.

In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity

The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC 50s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E 1S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.

Structure–Activity Relationships for Triphenylethylene Antiestrogens on Hepatic Phase-I and Phase-II Enzyme Expression

To better understand the mechanism(s) by which tamoxifen induces rat hepatic CYPIIB2 and suppresses GSTA1, structure–activity studies were performed. Compounds employed in these studies included: tamoxifen, fixed-ring tamoxifen, ethylated fixed-ring tamoxifen, pyrrolidino-tamoxifen, 4-iodotamoxifen, idoxifene, and toremifene. With respect to GSTA1 suppression, tamoxifen, fixed-ring tamoxifen, 4-iodotamoxifen, idoxifene, and toremifene were all potent suppressors of GSTA1, while ethylated fixed-ring tamoxifen and pyrrolidino-tamoxifen were completely without activity. The results suggest that the aminoethoxy side chain plays a crucial role in GSTA1 suppression, and that 4-iodination may potentiate this activity. With respect to induction of CYPIIB2, tamoxifen, fixed-ring tamoxifen, and ethylated fixed-ring tamoxifen were inducers of this enzyme, while toremifene and 4-iodotamoxifen were inactive, suggesting that the aminoethoxy side chain is not a structural determinant of CYPIIB2 induction. Because ethylated fixed-ring tamoxifen, toremifene, and 4-iodotamoxifen had differential activities in the two assays, we conclude that CYPIIB2 induction and GSTA1 suppression by triphenylethylenes are the result of two separate and distinct mechanistic pathways. Structure–activity relationships for GSTA1 suppression and CYPIIB2 induction were compared with previously published relationships for triphenylethylene: 1) estrogen receptor relative binding affinity; 2) calmodulin antagonism; 3) antiuterotrophic activity; and 4) antagonism of MCF-7 cell growth. No clear correlation was observed between the effects on CYPIIB2 and these other four activities, suggesting no relationship between the mechanisms responsible for these effects. Similarly, no precise correlation was observed between GSTA1 suppression and these other activities, although rough similarities were observed for relative binding affinity and antiuterotrophic activity. This suggests that the mechanisms responsible for CYPIIB2 induction and GSTA1 suppression are not related to the mechanisms of action for these other documented activities, and may represent different mechanistic pathways.

ChemInform Abstract: Synthesis, Uterotrophic, and Antiuterotrophic Activities of Some Estradiol Derivatives Containing Thiadiazole [cf. (VII)], Thiazoline [cf. (XII)], and Thiazolidinone [cf. (XIV)] Moieties .

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis, uterotrophic, and antiuterotrophic activities of some estradiol derivatives containing thiadiazole, thiazoline, and thiazolidinone moieties.

The effect of structural modification on the biological activity of hormones has been studied on five novel series of estradiol analogs bearing a variety of substituents at the 2-position of the steroidal nucleus. The synthesized compounds include 2-[2-(5-substituted amino-1,3,4-thiadiazol-2-yl)vinyl]estradiol 17 beta-acetate 5-9, 2-aroylmethylestradiols 10-12, 2-[2-aryl-2-(substituted thiocarbamoylhydrazono)ethyl]estradiols 13-18 and their cyclic thiazoline 19-24, and thiazolidinone derivatives 25-30. Among the products, the p-hydroxybenzolmethylestradiol 12 exhibited the highest antiestrogenic activity of 63%. It also elicited 34% of the uterotrophic activity of estradiol.

D-Ring alkylamine derivatives of estradiol: effect on er-binding affinity and antiestrogenic activity

A series of 17α-, 15α-, and 15β-(butyl methyl alkylamide)-estradiol derivatives ( 4–10) were synthesized from estrone and tested for the estrogen receptor binding affinity, uterotrophic activity, and antiuterotrophic activity. By moving the alkylamide side chain from B-ring (7α-position) or C-ring (11β-position) to D-ring (17α, 15α or 15β-positions) a dramatical decrease of the RBA and no antiestrogenic activity in uterine weight assay was observed. These results extend to D-ring the SAR study of this family of steroid antiestrogens. In addition, we also correct the C15-stereochemistry of compounds 5–10, which was incorrectly attributed in a previous paper.

Synthesis and evaluation of azole-substituted tetrahydronaphthalenes as inhibitors of P450 arom, P450 17, and P450 TxA2.

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH3 substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C1-spacer between the rings (compounds 2-26). The compounds were tested in vitro for inhibition of the three targets enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA2 (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition P450 18 (bovine adrenal mitochondria), P450 scc (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vitro, selected compounds were examined in Sprague Dawley rats regarding P450 TxA2 inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre-and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found; 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone (4) and 7-OCH3-2-(imidazol-4-ylmethyl)-tetralin (12) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12, the 6-OCH3 derivative (compound 11) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA2: 2-(imidazol-1-ylmethyl)-1-tetralone (13) is a selective inhibitor of P450 TxA2, whereas 7-OCH3-2-(imidazol-1-ylmethyl)-tetralin (17) as well 2-(imidazol-1-ylmethyl)-tetralin (16) and 7-OCH3-2-imidazol-1-yl-3, 4-dihydronaphthalene (25) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.

RU 58 668, a new pure antiestrogen inducing a regression of human mammary carcinoma implanted in nude mice

RU 58 668, a new steroidal antiestrogen, has been synthesized. Its in vitro and in vivo pharmacological activities have been compared to those of tamoxifen and ICI 182,780. In vitro, it displayed affinities for human and murine estrogen receptors equivalent to those of 4-hydroxy-tamoxifen, along with moderate affinities for progestin and glucocorticoid receptors. RU 58 668 proved to be a potent antiproliferative agent on MCF-7 cells stimulated by estradiol, or by exogenous or endogenous growth factors (IC 50, 0.01 nM). It also inhibited the growth of the insulin-stimulated T47D cell line. In vivo, RU 58 668 displayed a total antiuterotrophic activity in mice or rats without exhibiting any agonistic effect. Moreover, RU 58 668 was the only antiestrogenic compound tested so far to be able to induce a long term regression of human mammary MCF-7 tumors implanted in nude mice, suggesting its potential use for the treatment of advanced breast cancer.

Synthesis and biological activity of 17α-alkynylamide derivatives of estradiol

Seven estradiol (E 2) derivatives with an alkynylamide side chain at the 17α position were synthesized starting from ethynylestradiol (EE 2). The main chemical step was the coupling reaction of the acetylide ion of EE 2 with carbon dioxide, glutaric anhydride or bromoalkyl ortho ester. The synthesis of these compounds is fast (3–6 steps according to the compound) and is easily achieved with good yield. Five compounds with different side chain lenghts were evaluated for uterotrophic and antiuterotrophic activity in the CD-1 mouse. None of the tested compounds shows estrogenic activity in this sensitive in vitro system. At low doses (1 and 3 μg), a 14–57% inhibition of E 2-induced uterine growth was observed while no additional inhibition was observed at the 10, 20 and 30 μg doses. In human breast carcinoma cells in culture, all compounds show estrogenic activity at high concentrations while only compound 39 ( N-buty, N-methyl-8-[3′,17′ β-dihydroxy estra-1′,3′,5′(10′)-trien-17′ α-yl]-7-octynamide) possesses antiproliferative or antiestrogenic effects. No significant correlation could be demonstrated between alkynylamide side chain length and estrogenic or antiestrogenic activity. Among the compounds tested, the derivative of EE 2 possessing a five-methylene (CH 2) side chain (compound 39) possesses the best antiestrogenic activity (44 ± 7% in the CD-1 mouse uterus assay at the 3μg dose and 57 ± 4% at 0.1 nM in human ZR-75-1 cancer cells in culture).

Synthesis and antiestrogenic activity of the compounds related to the metabolites of (Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(4-isopropylphenyl)-1-butenyl)phenyl monophosphate (TAT-59).

The metabolites of (E) [corrected]-4-[1-[4-[2-dimethylamino)ethoxy]phenyl]- 2-(4-isopropylphenyl)-1-butenyl]phenyl monophosphate, TAT-59, (1), a potent antitumor agent for hormone-dependent tumors, and derivatives of TAT-59 were synthesized to confirm its proposed structure. The structure and the Z-configuration of the metabolites (2a-8a) were confirmed by comparison with synthesized authentic compounds. All of the metabolites and the derivatives of TAT-59 were tested for a binding affinity toward estrogenic receptors in vitro and antiuterotrophic activity in vivo. Most of the metabolites possessed remarkable binding affinity toward estrogenic receptors as well as fairly good antiuterotrophic activity.

Derivatives of ethynylestradiol with oxygenated 17α-alkyl side chain: Synthesis and biological activity

The coupling reaction of an acetylide ion with alkyl bromide or δ-valerolactone was used to synthesize twelve 1 17α-derivatives of ethynylestradiol having various 17α-side chain lengths and, except one, having mono- or di-oxygenated function on the side chain. All compounds had low (0.01–1.79%) relative binding affinity (RBA) for the rat uterine estrogen receptor. The highest RBA were obtained for compounds 26 (1.79%), 30 (1.55%) and 19 (0.42%). The length and polarity of the side chain decreases the affinity for the estrogen receptor. The in vivo estrogenic activity was measured on mouse uterine weight and was found to range from 0 to 35%, except for compound 30 (100%). The antiuterotrophic activity was measured by inhibition of estradiol-induced stimulation of uterine weight and was found to be 39% for compound 19, 25% for compound 26 and 0% for all other compounds. These two compounds ( 19 and 26) possess mixed agonist and antagonist activity.

Synthesis and biologic activities of 11β-substituted estradiol as potential antiestrogens

The effect of attachment of a dimethylaminoethoxy or a dimethylaminopropoxy group at the 11β-position of estradiol (E 2) on its relative binding affinity (RBA) to estrogen receptor (ER) and intrinsic biologic activity is described. The binding of 11β-[2-(N,N-dimethylamino)ethoxy]estra-1,3,5(10)-triene-3,17β-diol (4) and 11β-[3-(N,N-dimethylamino)propoxy]estra-1,3,5(10)-triene-3,17β-diol (5) to the ER from immature rat uterine tissue was measured relative to that of [ 3H]E 2 by a competitive binding assay. It was found that the 11β-substituted E 2 analogs have considerably lower RBA to ER than the corresponding parent compound. The intrinsic activity of compounds 4 and 5 were studied in terms of uterotrophic and antiuterotrophic activity. It was found that the uterotrophic activity of these compounds was drastically reduced compared with E 2. However, no antiuterotrophic activity was observed in these compounds at dosages ranging from 1 to 100 μ/rat/d. (Steroids 55:238–241, 1990).

Synthesis and biological activity of 4-methylestradiol

The synthesis of 4-methylestradiol (4-ME 2) was carried out by reductive aromatization of 4-methyl-1,4-androstadiene-3-one-17β-ol. The relative binding affinity of 4-ME 2 was found to be 10 and 25% of estradiol at 0 and 25°C, respectively. 4-ME 2 had considerably weaker uterotrophic activity relative to estrone and was found to have no antiuterotrophic activity.

Synthesis of PtCl 2 complexes of pyridylmethylamine ligands and their activity against hormone-dependent mammary carcinoma

Fifteen ligands of the pyridylmethylamine type and their PtCl 2 complexes were prepared, characterized and subjected to a screening system for evaluation of a specific activity against the hormone-dependent mammary carcinoma. To test the estrogenic activity of the ligands, the relative binding affinity (RBA, in vitro) and the uterotrophic and antiuterotrophic activities (mouse uterine weight test, in vivo) were determined. To study the cytotoxic effects, the PtCl 2 complexes were tested in vitro towards the hormone-independent human mammary carcinoma cell line MDA-MB 231 and in vivo towards the lymphocytic P 388 leukemia. Finally, there was a comparative test of ligands and PtCl 2 complexes in the hormone-independent MXT (3.2) Ovex mammary carcinoma and the hormone-dependent MXT M3.2 mammary carcinoma.

ChemInform Abstract: Influence of Alkyl Chain Ramification on Estradiol Receptor Binding Affinity and Intrinsic Activity of 1,2‐Dialkylated 1,2‐Bis(4‐ or 3‐hydroxyphenyl)ethane Estrogens and Antiestrogens.

The influence of a symmetrical introduction of CH3 substituents in the alpha or beta positions of the 1,2-dialkyl-1,2-bis(4-hydroxyphenyl)ethane estrogens hexestrol (ethyl, HES) and octestrol (n-propyl, OCES) [isopropyl (1), tert-butyl (2), sec-butyl (3), isobutyl (4)] and the 1,2-dialkyl-1,2-bis(3-hydroxyphenyl)ethane antiestrogens metahexestrol (ethyl, MetaHES) and metaoctestrol (n-propyl, MetaOCES) [isopropyl (5), tert-butyl (6), sec-butyl (7), isobutyl (8)] on estradiol receptor (E2R) binding affinity and intrinsic activity is described. The synthesis of compounds 1-8 was accomplished by reductive coupling of (a) the corresponding alpha-alkylbenzyl alcohols with TiCl3/LiAlH4 and separation of the meso diastereoisomers (compounds 2-4, 7, and 8), (b) alpha-tert-butyl-3-methoxybenzyl chloride with CoCl2/EtMgCl and isolation of the meso configurated isomer (6), and (c) the isopropyl phenyl ketones with TiCl4/Zn and subsequent hydrogenation of the corresponding cis-hex-3-enes (compounds 1 and 5). The binding affinity of 1-8 to the calf uterine E2R was measured relative to that of [3H]E2 by a competitive binding assay. Compounds 1 and 5 showed relative binding affinity (RBA) values exceeding those of HES and MetaHES, respectively. All other derivatives showed RBA values smaller than the corresponding parent compounds. The intrinsic activity was monitored in terms of uterotrophic and antiuterotrophic activity. It is striking that the introduction of a CH3 group in the alpha positions of MetaHES and MetaOCES led to compounds with full intrinsic activity (5-7), i.e., estrogens without antiestrogenic properties. No correlation between E2R binding affinity and intrinsic activity was found.