Medicinal Chemistry of Steroids: Estrogens Focus - Steroid Lecture 2 PCOL 826B
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Questions and Answers

What is the function of tamoxifen in relation to ER-alpha?

  • Inhibits the transcriptional activity of ER-alpha (correct)
  • Enhances the recruitment of co-activators to ER-alpha
  • Induces conformational changes preventing ER-alpha binding to anti-estrogen drugs
  • Activates ER-alpha to bind to estrogen response elements

    • What is the effect of estradiol versus tamoxifen on ER-alpha?

  • Estradiol is transcriptionally active, while tamoxifen is transcriptionally inactive (correct)
  • Both estradiol and tamoxifen are transcriptionally inactive
  • Estradiol is transcriptionally inactive, while tamoxifen is transcriptionally active
  • Both estradiol and tamoxifen are transcriptionally active

    • Which compound is a prodrug that requires hepatic O-demethylation to become an active ER ligand?

  • Estradiol
  • Diethylstilbestrol
  • Raloxifene
  • Mestranol (correct)

    • What is the role of coactivators in ER activation?

    <p>Enhance the transcriptional activity of ER by binding to it</p> Signup and view all the answers

    Which type of substituent on the D-ring enhances the oral availability of estrogens?

    <p>17a-ethinyl substituent</p> Signup and view all the answers

    What effect does the binding of anti-estrogens like tamoxifen have on estrogen receptor-alpha?

    <p>Prevents the recruitment of co-activators to ER-alpha</p> Signup and view all the answers

    What is the mechanism of action of fulvestrant (ICI-182780) on estrogen receptor-alpha?

    <p>Prevents binding of co-activators to ER-alpha</p> Signup and view all the answers

    What is the function of raloxifene in relation to estrogen receptor signaling?

    <p>Partially transcriptionally active as an ER ligand</p> Signup and view all the answers

    Which of the following is a common use of drugs targeting the estrogen receptor?

    <p>Treating osteoporosis</p> Signup and view all the answers

    Which type of ER modulator is used to treat breast cancer chemoprevention and chemotherapy?

    <p>ER antagonists</p> Signup and view all the answers

    What is the most appropriate function of estrogen receptor alpha (ERa)?

    <p>Transcription factor activation</p> Signup and view all the answers

    Where are the Zinc atoms contained in the estrogen receptor?

    <p>In the DNA binding domain</p> Signup and view all the answers

    Which of the following tissues expresses both ERa and ERb?

    <p>All of the above</p> Signup and view all the answers

    Which of the following best describes the estrogen receptor (ER) function?

    <p>A ligand-activated transcription factor</p> Signup and view all the answers

    What is a common treatment for oral contraception that targets the estrogen receptor?

    <p>ER agonists</p> Signup and view all the answers

    Which of the following is true about estrogen receptor signaling?

    <p>It activates transcription factors to regulate gene expression</p> Signup and view all the answers

    What is the main difference between tamoxifen and fulvestrant in terms of ER binding?

    <p>Fulvestrant competes for ER binding and induces ER degradation while tamoxifen only competes for ER binding</p> Signup and view all the answers

    Which function does fulvestrant not perform on the estrogen receptor?

    <p>Inducing ER dimerization</p> Signup and view all the answers

    Which statement best describes the function of fulvestrant?

    <p>Fulvestrant is a pure estrogen antagonist without agonist properties</p> Signup and view all the answers

    Which type of breast cancer is fulvestrant used to treat?

    <p>Estrogen receptor-positive metastatic breast cancer</p> Signup and view all the answers

    Which of the following statements about fulvestrant is true?

    <p>Fulvestrant bears a penta-fluorinated alkyl-substituent</p> Signup and view all the answers

    In which scenario would fulvestrant be used?

    <p>When hormonal therapies such as tamoxifen have failed</p> Signup and view all the answers

    What is the impact of fulvestrant on estrogen signaling?

    <p>Fulvestrant completely inhibits estrogen signaling</p> Signup and view all the answers

    Which of the following is a common use for fulvestrant?

    <p>Treatment of estrogen receptor-positive metastatic breast cancer in postmenopausal women</p> Signup and view all the answers

    What is the function of 4-hydroxytamoxifen in breast tissue?

    <p>It acts as an antagonist to inhibit transcription of estrogen-responsive genes.</p> Signup and view all the answers

    What gene variant may impact the effectiveness of tamoxifen in some patients?

    <p>CYP2D6</p> Signup and view all the answers

    What potential side effect has tamoxifen been linked to in some women?

    <p>Endometrial cancer</p> Signup and view all the answers

    What is the role of CYP2D6 in tamoxifen metabolism?

    <p>It converts tamoxifen into its more potent metabolites.</p> Signup and view all the answers

    What is the approved use of raloxifene in postmenopausal women?

    <p>Treatment and prevention of osteoporosis</p> Signup and view all the answers

    What other use of raloxifene was approved by the FDA in 2007?

    <p>As a chemopreventive medication against invasive breast cancer</p> Signup and view all the answers

    What is the effect of tamoxifen on bone tissue?

    <p>It has anti-osteoporotic effects.</p> Signup and view all the answers

    What are poor metabolizers of tamoxifen characterized by?

    <p>Lower levels of endoxifen and poorer clinical outcomes.</p> Signup and view all the answers

    Which of the following estrogenic agents can undergo enterohepatic recycling?

    <p>1, 2, 3, 4</p> Signup and view all the answers

    What is the route of administration for conjugated equine estrogens (CEE)?

    <p>Oral, transdermal, or intravaginal</p> Signup and view all the answers

    What is the purpose of the estradiol transdermal system?

    <p>To release estradiol through a rate-limiting membrane continuously upon application to intact skin</p> Signup and view all the answers

    What are the five estrogenic agents that target the estrogen receptor?

    <p>Equilin sulfate, 17a-dihydroequilin, estrone sulfate, equilenin, estradiol</p> Signup and view all the answers

    What is the mechanism of action of the estradiol transdermal patch?

    <p>The estradiol transdermal patch releases estradiol in a continuous manner</p> Signup and view all the answers

    What is the purpose of the enterohepatic recycling of E1-S?

    <p>To increase the half-life of E1-S</p> Signup and view all the answers

    What is the purpose of hormonal replacement therapy (HRT) for the treatment of menopausal symptoms?

    <p>To replace the hormones that are no longer produced by the body after menopause</p> Signup and view all the answers

    What is the advantage of using transdermal patches for systemic delivery of hormones?

    <p>Transdermal patches bypass the first-pass metabolism in the liver</p> Signup and view all the answers

    Study Notes

    Estrogen Receptor Signaling

    • Estrogen Receptor (ER) is a ligand-activated transcription factor.
    • Estrogen Response Element (ERE) is present in the promoter region of target genes.
    • ERα (Estrogen Receptor alpha) and ERβ (Estrogen Receptor beta) are two subtypes of ER.

    ERα Ligand Binding

    • Estradiol (E2) is a natural ligand that binds to ERα, causing a conformational change that activates transcription.
    • Tamoxifen and fulvestrant are anti-estrogens that bind to ERα, causing a conformational change that prevents the recruitment of co-activators.
    • 4-OH-tamoxifen is an active metabolite of tamoxifen.

    Estrogen Receptor Ligands

    • Estradiol (E2) is a potent ER ligand.
    • 17α-ethinylestradiol (EE) is a metabolically stable ER ligand.
    • Raloxifene is a selective ER modulator (SERM) that targets osteoporosis and breast carcinogenesis.
    • Diethylstilbestrol (DES) is a synthetic ER ligand.

    Targeting ERα

    • Estradiol and tamoxifen have different effects on ERα, with estradiol causing a transcriptionally active conformation and tamoxifen causing a transcriptionally inactive conformation.
    • Fulvestrant is a pure ER antagonist that binds to ERα, competing with estradiol, and also induces ERα degradation.

    Steroid Hormone Receptors

    • The classic model of steroid hormone receptors involves ligand binding, causing a conformational change that activates transcription.
    • ERα is a ligand-activated nuclear transcription factor.

    Exam Questions

    • Fulvestrant is a potent anti-estrogen that binds to ERα, competing with estradiol, and induces ERα degradation.
    • Tamoxifen is metabolized by CYP2D6 to 4-OH-tamoxifen, which is a more potent metabolite.

    Enterohepatic Recycling

    • Enterohepatic recycling of estrogens occurs through intestinal microbial deconjugation and reuptake of free estrogens.
    • Estrone sulfate (E1-S) and conjugated equine estrogen (CEE) undergo enterohepatic recycling.

    Hormonal Replacement Therapy

    • Hormonal replacement therapy is used to treat menopausal symptoms.
    • Estrogen-only therapy involves the use of estradiol acetate, conjugated equine estrogens (CEE), or micronized 17β-estradiol.
    • Estrogen/progestin combinations involve the use of CEE + medroxyprogesterone acetate (MPA) or ethynylestradiol (EE) + norethindrone.

    Transdermal Patches

    • Transdermal patches are used for systemic delivery of estrogen and other cardiovascular agents, analgesics, and hormones.
    • Estradiol transdermal system is designed to release estradiol continuously upon application to intact skin.

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    PCOL 826B Steroid Lecture 2 (2022) PDF

    Description

    Explore drugs targeting the estrogen receptor, including their use in oral contraception, breast cancer chemoprevention, chemotherapy, infertility treatment, hormone replacement therapy [HRT], and osteoporosis. Learn about SERM [selective ER modulators], ER agonists, and ER antagonists. Study the medicinal chemistry of Estrogen Receptor alpha.

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