Time-related effects of a triphenylethylene antiestrogen on estrogen-induced changes in uterine weight, estrogen receptors, and endometrial sensitivity in rats

Time-related estrogen antagonistic action of a single oral contraceptive (1.25 mg/kg) dose of the triphenylethylene antiestrogen centchroman was determined in ovariectomized immature rats. Tamoxifen and nafoxidine were used for comparison. A single oral administration of centchroman followed by three doses of estradiol-17β (1 μg/d, s.c.) caused significant dose-dependent inhibition in estradiol-17β-induced increase in uterine weight and nuclear and cytosolic estrogen receptors. But the inhibition at anti-implantation dose was evident only if estradiol-17β treatment was initiated not later than 48 h post-antiestrogen. Alternatively, when antiestrogen treatment was followed by a single dose of estradiol-17β between days 2–7, a synergistic action, typical of antiestrogens possessing weak estrogen agonistic activity, was observed. In immature rats in which a condition mimicking preimplantation was produced by estradiol-17β (0.5 μg/d, s.c.) priming on days -2 and -1, followed by progesterone (1 mg/d, s.c.) and an endometrial sensitizing dose (0.5 μg/d, s.c.) of estradiol-17β at 1600 h on day 4, anti-implantation dose of centchroman administered on day 1, too, failed to inhibit uterine weight gain induced by sensitizing dose of estradiol-17β, but caused marked inhibition in endometrial sensitivity to a deciduogenic stimulus and decidualization and weight gain of traumatized uterine horn 96 h post-traumatization over non-traumatized horn was only about 150% (725% in controls). Inhibition in endometrial sensitivity and decidualization was evident when the interval between antiestrogen treatment and sensitizing estradiol was <126 h. Pinopods were present on endometrial surface on day 5 whether or not priming and/or sensitizing doses of estradiol were administered, but decidual response was mild if either of these doses of estradiol-17β was deferred. Findings suggest that: (a) duration of antiestrogenic action of single anti-implantation dose of centchroman in rat was about 126 h, which in ovariectomized immature rats was evident only when a condition mimicking preimplantation was produced and the antiestrogenic response was based on inhibition in estradiol-induced endometrial sensitivity and not uterine weight gain; (b) priming as well as sensitizing estrogen were essential to get optimal decidual responses; (c) appearance of pinopods on endometrial surface may not be related to endometrial sensitivity; and (d) tamoxifen and nafoxidine appear slightly longer acting with duration of antiestrogenic action of 150 h.     

Effect of centchroman on the uptake of tritiated estradiol-17β and progesterone by different tissues of ovariectomized rats

The effects of centchroman on the uptake of 6,7-³H-estradiol and 1,2,6,7-³H-progesterone by different tissues in ovariectomized young adult rats were studied. Pre-treatment with centchroman inhibited the uptake of radioactive estradiol by the hypothalamus pituitary, uterus, fallopian tube, adrenal and liver, but not that by plasma. In the other set of experimental animals, centchroman also counteracted the estradiol benzoate-induced increase in the weight of the pituitary, uterus and vagina, although administration of centchroman alone increased the weight of the pituitary and uterus in ovariectomized rats. These results may be explained on the basis of competitive inhibition of estrogen at target tissue level.

Compared to the control group, the uptake of radioactivity as pure progesterone was more in all the tissues except the vagina and liver of the animals pre-treated with centchroman, whereas the uptake of total radioactivity was increased in the liver and plasma but remained unchanged in other tissues. The results indicate that centchroman, which has been claimed to have an anti-progestational action, did not accelerate the metabolism or elimination of progesterone, nor did it interfere with the uptake of progesterone by the target tissue.     

Effect of concurrently coadministered drugs on the pharmacokinetic/pharmacodynamic profile of centchroman, a nonsteroidal oral contraceptive, in rats

INTRODUCTION: Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of centchroman in female Sprague-Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide. MATERIALS AND METHODS: The pharmacological activity of centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared. RESULTS: In pharmacological interaction studies, centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability (F) and volume of distribution (V(d)) in some situations. CONCLUSIONS: The results indicate that there is no direct link between the altered pharmacokinetics of centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with centchroman and that caution should be taken in clinical practice.     

Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of centchroman in rats

Centchroman (Ormeloxifene) is a nonsteroidal, selective estrogen receptor modulator, oral contraceptive and anticancer agent, and is intended for long-term use by women. In view of its vast clinical application and the interaction of steroidal oral contraceptives with certain commonly used therapeutic agents, evaluation of interaction of certain concomitantly administered therapeutic agents (ibuprofen, rifampicin, diazepam, salbutamol, nifedipine, paracetamol, haloperidol, and tetracycline), in terms of both the postcoital contraceptive efficacy and pharmacokinetic profile, with centchroman was undertaken in female Sprague-Dawley rats. Among the representatives from each commonly used therapeutic category, interaction (pharmacokinetic) was observed with ibuprofen (60 mg/kg, twice daily), haloperidol (0.7 mg/kg, twice daily), and tetracycline (140 mg/kg, twice daily) coadministration on Days 1 through 5 postcoitum. Of these three therapeutic agents, only tetracycline interfered with the contraceptive efficacy of centchroman. It reduced the bioavailability of centchroman and its active metabolite by increasing their excretion through bile and feces. Increased metabolite excretion on tetracycline coadministration indicates the enterohepatic recirculation of the metabolite, not the parent drug. However, the effect of tetracycline was negated by the inclusion of lactic acid bacillus spores in the regimen.     

Clinical pharmacokinetics and interaction of centchroman — A mini review

This article provides a brief review of the information available regarding the published pharmacokinetics data for the nonsteroidal, once-a-week oral contraceptive, centchroman (INN: ormeloxifene). This agent is a unique need-oriented contraceptive agent which is included in the National Family Welfare Programme of India. Since 1991, centchroman has been used as a need-oriented contraceptive and is being given for treating dysfunctional bleeding of the uterus. Information regarding absorption, tissue distribution, elimination and kinetic interactions is discussed.     

Action of an estrogen antagonist in intact and ovariectomized rats

The uterine uptake of tritiated estradiol-17β, at both low (0.6 μg/ kg) and high doses (2.4 μg/kg), in intact or ovariectomized immature rats was inhibited in a dose-related manner by the estrogen antagonist, CN-55,945-27 (l-(2-&p-[α(p-methoxyphenyl)-β-nitrostyryl]-phenoxy&-ethyl)-pyrrolidine monocitrate). With low dose estrogen treatment, CN-55,945-27 did not inhibit estradiol-17β-induced uterine weight increases in the intact rats. However, in the ovariectomized rats, the high dose of CN-55, 945-27 inhibited the low dose estrogen stimulation of uterine weight increase. When the high dose of estrogen was used, a direct correlation existed between the CN-55,945-27 dose-related reduction of the uptake of the tritiated estradiol-17β and its inhibition of the estrogen induced uterine growth in both the intact and ovariectomized rats. These data and the differences observed between the intact and ovariectomized rats in the uterine uptake of tritiated estradiol-17β and in the degree of stimulation over the control uterine weights suggest that a combination of the presence of endogenous estrogen or other substances (intact rats) and an alteration of the affinity of the uterine estrogen receptors are involved. The patterns of uptake of tritiated estradiol-17β by the pituitaries in the intact and ovariectomized rats and of the inhibition of this uptake by CN-55,945-27 were similar to those observed for the uteri. Uptake of tritiated estradiol-17β by the hypothalami and the effect of CN-55,945-27 on this uptake did not produce the same patterns observed for the uteri and pituitaries. Differences in the hypothalamic estrogen uptake between the intact and ovariectomized rats were not evident. CN-55,945-27 inhibition of this hypothalamic estrogen uptake occurred only in the intact rats treated with the high dose of estradiol-17β. These data indicate that there is an ovarian (?) substance(s) which regulates the sensitivity or affinity of the uterine and pituitary estrogen receptors and which can regulate the action of estrogen antagonists in the hypothalamus in immature rats.     

Lupus: why women?

Estrogens are believed to play a role in the etiology of both human and murine systemic lupus erythematosus (lupus, SLE), presumably through the agency of their cellular receptor proteins. There is now considerable interest in the molecular mechanism of action of estrogens in immune tissues, particularly with regard to autoimmune disorders, which are generally more prevalent in women. In this laboratory, an attempt is being made to characterize estrogen receptors in murine models of SLE, namely NZB/W and MRL/MP-lpr/lpr mice, and to try to relate this to estrogen receptor function in vivo. It is hypothesized that estradiol (E(2)), through its receptors, mediates the progression of murine SLE and that in autoimmune disease, the estrogen receptor is functionally or structurally changed, or both. Initial studies suggest there are differences in estrogen receptors between BALB/c mice, which do not get autoimmune disease, and two strains that do, MRL/MP-lpr/lpr and NZB/W mice. There is evidence that in at least one model of SLE, the normal regulation of estrogen action by progesterone may be impaired. In several laboratories, attempts are being made to relate estrogen action to immune function and to autoimmune diseases. The study of estrogen action on the immune system may lead to the development of treatments that attenuate the immunostimulant effects of E(2) in autoimmune diseases such as SLE.     

Determination of estrogenic/antiestrogenic potential of antifertility substances using rat uterine peroxidase assay.

The effect of three compounds (clomiphene citrate, centchroman, embelin) and plant-derived methanolic extracts (Abutilon indicum and Butea monosperma) was studied on uterotropic and uterine peroxidase activities in ovariectomized rats. It was observed that these two parameters were highly correlated in response to treatment with these test materials and also to estradiol. It was suggested that the uterine peroxidase assay could be utilized as a biochemical parameter in the screening of new antifertility agents for their estrogenic/antiestrogenic properties.     

镉对大鼠子宫雌激素受体影响的体外研究

目的研究镉对子宫雌激素受体结合容量影响,并评价其环境内分泌干扰作用。方法制备大鼠子宫细胞质雌激素受体;运用正交实验设计[L16(45)]进行单剂量配基结合试验研究两因素——镉的浓度和预先孵育时间对雌二醇(E2)结合雌激素受体(ER)的最大结合容量(Bmax)影响;用竞争结合抑制试验,计算镉的IC50值,并以己烯雌酚为参照品计算相对亲和力(RBA),研究镉与ER的结合能力。结果体外不同浓度的镉(0、10-3、10-5、10-7mol/L)与孵育不同时间(0、30、60、90min)对E2与ER的最大结合位点数(Bmax,单位为pmol/mg蛋白)的改变均无统计学意义(P>0.05),同时也未见体外不同浓度的镉与孵育不同时间有交互作用,差异无统计学意义(P>0.05);其中0、10-3、10-5、10-7mol/L浓度的镉孵育0min的Bmax分别为203.15±75.16、203.41±22.78、220.82±45.35、209.10±49.66;孵育30min的Bmax分别为215.67±92.97、139.79±53.78、205.27±23.60、172.63±55.09;孵育60min的Bmax分别为197.11±50.68、203.24±66.33、183.92±31.89、183.33±32.70;孵育90min的Bmax分别为229.69±76.88、175.70±70.28、164.26±24.46、150.78±65.97。氯化镉的半数抑制浓度(IC50)为10-4～10-3mol/L之间,Cd与ER结合的RBA约为DES的10-6～10-7。结论镉对E2与子宫雌     

Pyridoxal supplementation reduces cell proliferation and DNA synthesis in estrogen-dependent and -independent mammary carcinoma cell lines

In previous studies, decreased growth of tumor cells by vitamin B-6 treatment has been attributed to modulation of steroid hormone action. Therefore, the growth-inhibiting properties of pyridoxal (PL) supplementation were studied in estrogen receptor-positive, MCF-7 and T-47D, and estrogen receptor-negative, BT-20, breast cancer cell lines. Cell counting and [3H]thymidine incorporation into DNA were used to assess growth, and analysis of pS2 expression was used to determine whether PL supplementation affected estrogen action. Treatment with 100 or 300 mM PL resulted in dose-dependent decreases in total cell numbers in the absence (26-85% and 72-98%, respectively) and presence (38-42% and 88-98%, respectively) of estradiol in all cell lines studied compared with control cells cultured without PL supplementation. Similar decreases in DNA synthesis were observed in response to PL supplementation. Incorporation of [3H]thymidine into DNA of cells cultured with 100 or 300 microM PL was decreased by 30-90% and 96-99%, respectively, in the absence and by 32-40% and 82-99%, respectively, in the presence of estradiol. Northern analysis showed that expression of the estrogen-sensitive gene pS2 was not affected by either concentration of PL. These results indicate that PL supplementation regulates breast cancer cell growth in vitro via a mechanism that appears to be steroid independent.     

Pyridoxal Supplementation Reduces Cell Proliferation and DNA Synthesis in Estrogen-Dependent and -IndependentMammary Carcinoma Cell Lines

In previous studies, decreased growth of tumor cells by vitamin B-6 treatment has been attributed to modulation of steroid hormone action. Therefore, the growth-inhibiting properties of pyridoxal (PL) supplementation were studied in estrogen receptor-positive, MCF-7 and T-47D, and estrogen receptor-negative, BT-20, breast cancer cell lines. Cell counting and [³H]thymidine incorporation into DNA were used to assess growth, and analysis of pS2 expression was used to determine whether PL supplementation affected estrogen action. Treatment with 100 or 300 mM PL resulted in dose-dependent decreases in total cell numbers in the absence (26-85% and 72-98%, respectively) and presence (38-42% and 88-98%, respectively) of estradiol in all cell lines studied compared with control cells cultured without PL supplementation. Similar decreases in DNA synthesis were observed in response to PL supplementation. Incorporation of [3H]thymidine into DNA of cells cultured with 100 or 300 μM PL was decreased by 30-90% and 96-99%, respectively, in the absence and by 32-40% and 82-99%, respectively, in the presence of estradiol. Northern analysis showed that expression of the estrogen-sensitive gene pS2 was not affected by either concentration of PL. These results indicate that PL supplementation regulates breast cancer cell growth in vitro via a mechanism that appears to be steroid independent.     

Optimization of contraceptive dosage regimen of Centchroman

Centchroman (Ormeloxifene), a non-steroidal oral contraceptive, is used at a dose of 30 mg once a week. To prevent failures in the beginning of the therapy, it is recommended that a dose of 30 mg twice a week for 12 weeks be administered to build up adequate blood levels. The present study was undertaken to simplify the dosing schedule without sacrificing the purpose of twice a week dosing regimen, using modeling and measurement approaches. The drug was given to 60 female volunteers who were divided into seven groups: group I, 30 mg weekly; group II, 30 mg twice a week; group III, 30 mg twice a week for 12 weeks followed by 30 mg weekly; group IV, 30 mg twice a week for 6 weeks followed by 30 mg weekly; group V, 60 mg weekly; and groups VI and VII, single 60 mg loading dose followed by 30 mg weekly doses. The blood samples were collected and analyzed by HPLC. In group I, mean trough concentrations of centchroman and its active metabolite, 7-desmethyl centchroman, were comparable to the steady-state trough concentrations in groups III, IV, VI, and VII. The metabolite to parent drug ratio remained constant in all the groups. The pharmacokinetic parameters in group VII were comparable to those reported after a single 30 mg dose. Dosage regimen VI was more convenient and provided better pregnancy protection (Pearl index 1.18; unpublished report) than regimen III, which is currently on the market and, thus, could be effectively used for contraception.     

High-density lipoproteins: effects of alcohol, estrogen, and phytoestrogens

Plasma high-density lipoproteins (HDL) play an important role in the reverse cholesterol transport pathway. Factors affecting plasma HDL levels may be important, therefore, in the prevention of cardiovascular disease. Among the lifestyle and environmental factors that have been shown to increase HDL cholesterol are moderate alcohol intake and estrogen administration. Phytoestrogens, molecules of plant origin that resemble estrogen and act as weak estrogens, do not have a clear effect on HDL cholesterol. The molecular mechanisms of action of alcohol, estrogen, and phytoestrogens on HDL are under investigation.     

Uterine molecular responses to bisphenol A treatment before and after decidual induction in pseudopregnant rats

The results of the study demonstrate that the weak estrogenic action of bisphenol A (a daily subcutaneous dose of 200 mg/kg on 4 consecutive days, administered before or after decidual induction that occurs on day 4 of pseudopregnancy) on deciduoma growth in pseudopregnant Sprague-Dawley rats, was functionally associated with the hormonal status of the uterus. Whereas bisphenol A displayed uterotrophic action during the pre-decidual, estrogen related period, it inhibited decidual growth and progesterone secretion during the post-decidual, progesterone-dominated period. The estrogenic action of bisphenol A on uterine decidual growth was not correlated with the reduced levels of estrogen receptor binding sites and mRNA expression, nor the unchanged serum estradiol concentrations. BPA action appeared to be antagonized by progesterone.     

Puerarin exerted anti-osteoporotic action independent of estrogen receptor-mediated pathway

Puerarin, a daidzein-8-C glucoside, is the major isoflavonoid in Kudzu (Pueraria lobata), and is unique in that it contains C-C conjugated glucose at position 8 of the isoflavonoid structure. A puerarin diet at a dose of 5 mg/kg b.w./d to fed ovariectomized mice for 2 mo diminished the urinary deoxypyridinoline, a typical bone-degradation product. Since the bone absorption marker, serum tartarate-resistant acid phosphatase (TRAP) activity of puerarin-fed mice decreased but the bone formation marker, osteocalcin level, did not alter, the puerarin diet was proved to specifically depress the bone absorption, but not the overall bone metabolism. In accordance with that results, the femur structure of puerarin-fed mice was restored compared with that of puerarin-free diet mice. The atrophied uterine due to low estrogen (E2) level after ovariectomy was not restored by the puerarin diet, suggesting that puerarin exerted the anti-osteoporotic action through a non estrogen receptor (ER) mediated-pathway, in vivo. The growth of an ER-positive human breast cancer cell, MCF-70, was not enhanced by puerarin, suggesting that puerarin did not show estrogen-like action on MCF-7 cells, even at a ten thousand times higher concentration than that of E2. Furthermore, ICI182,780 (ICI), an estrogen antagonist, suppressed the enhanced growth of MCF-7 cells by E2, but not that by puerarin. In an ER-binding assay, puerarin was proved not to bind to ERα or β, or if all, extremely weakly, although daidzein, an aglycon of puerarin, showed a little stronger binding compared with puerarin. All these results strongly indicate that puerarin exerts its anti-osteoprotic action independently of the ER-mediated pathway.     

内源性雌、孕激素与人乳头瘤病毒在宫颈癌发生中的协同作用研究

目的探讨雌、孕激素对宫颈癌发生的作用及其与人乳头瘤病毒(HPV)的协同作用。方法采用热启动PCR和ELISA法，对141例宫颈癌和129名健康妇女进行了HPVs、HPV16、雌二醇(E2)和孕酮(P)含量的测定。结果宫颈癌组HPVs和HPV16的阳性率分别为75．2％和46．8％，显著高于健康对照组；血清中E2和P的平均浓度均为病例组高于对照组，差异有统计学意义，特别是E2水平与宫颈癌之间呈剂量反应关系；E2与HPVs之间呈正相加交互作用，且有统计学意义。结论HPV感染，特别是HPV16感染在宫颈癌发生中起重要作用；内源性雌激素的升高可增加宫颈癌发生的危险性；高水平的雌二醇和HPV感染对宫颈癌的发生可能具有协同作用。     

Hormone therapy for breast cancer

Breast cancer is a hormone responsive disease, and its proliferation and progression correlate with estrogen. Estrogen binds to estrogen receptor and induces various target genes, thus promoting proliferation of breast cancer cells. Therefore, the strategy of endocrine therapy is the blockade of estrogen action. We can use a luteinizing hormone releasing hormone agonist and aromatase inhibitor as an interruptor of supply, tamoxifen as an inhibitor of estrogen receptor, and medroxyprogesterone acetate with an anti-estrogen action. In this article, we review endocrine therapy for breast cancer patients based on recent clinical trials.     

A sensitive zonagenetic assay for rapid in vitro assessment of estrogenic potency of xenobiotics and mycotoxins.

Mounting evidence confirms that hepatic biosynthetic processes are essential for female sexual maturation in fish, which is directly controlled by estrogens. These oogenetic events (zonagenesis and vitellogenesis) are induced in both sexes by estrogens. In this paper, we report the induction of zona radiata (zr) proteins and vitellogenin in primary hepatocytes from Atlantic salmon (Salmo salar L.) exposed to xenoestrogens and mycotoxins. Cells were treated with doses of 1, 5, and 10 microM 4-nonylphenol (4-NP), o, p'-DDT, lindane ([gamma]-HCH), and bisphenol A (BPA), which all induced zr proteins and vitellogenin in an approximate dose-dependent manner. Hepatocytes were also treated with combinations of xenoestrogens at 1 or 2 microM, resulting in elevated levels of both zr proteins and vitellogenin, compared to single treatment. The estrogenic activity of the mycotoxin zearalenone (ZEA) and its metabolites [alpha]-ZEA) and ss-zearalenol (ss-ZEA)], with regard to zonagenesis and vitellogenesis, was assessed in this assay system. Mycotoxins were used at concentrations of 10, 100, or 1,000 nM. All induced zr proteins and vitellogenin, with [alpha]-ZEA being the strongest inducer. When cells were treated with xenoestrogens or mycotoxins in combination with an estrogen receptor inhibitor (ICI 182,780), the induction of both zr proteins and vitellogenin was inhibited in all cases. Thus, the reported estrogen effects are bonafide estrogen responses. Zona radiata proteins were more responsive than vitellogenin to both xenoestrogens and mycotoxins. The versatility and sensitivity of the hepatocyte assay demonstrates that biosynthesis of zr proteins provides a new supplementary method for estimating xenoestrogenicity and mycotoxin action.     

Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators

In an systematic attempt to develop novel Selective Estrogen Receptor Modulators (SERMs), chiral 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were designed based on an accepted pharmacophore model. Simpler prototypes, viz. racemic 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ols, were first synthesized to develop kinetic resolution to pure enantiomers. Simultaneously, a series of racemic 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were evaluated against estrogen-responsive human MCF-7 breast cancer cells, but the compounds were found to be moderately active. The lack of potency could be due to the molecular bulk resulting in inadequate fit at the receptor. Subsequently, the molecular motif was modified to achiral 1-(4-(2-(dialkylamino)ethoxy)benzyl)naphthalen-2-ols by removing the piperidinol moiety. Bioevaluation of this new series of compounds displayed significantly enhanced cytotoxicity against MCF-7 cells. A representative compound for this series showed estrogen receptor alpha binding activity and the action is that of an antagonist.