A report on Selective estrogen receptor modulator, Raloxifene and Estrogen receptor alpha

Tamoxifen, a nonsteroidal triphenylethylene antiestrogen and a widely used drug in the treatment of breast cancer.

Figure 2: Nolvadex (tamoxifen) 20-milligram tablets (UK)

Figure 3: The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

Figure 4: Structural basis for the mechanism of estrogen receptor agonist and antagonist action. The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, ) or antagonist 4-hydroxytamoxifen (bottom, ). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LBD (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif. Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

Figure 5: 4-hydroxytamoxifen (red) overlaid with 17β-estradiol (black)

Figure 6: Trans-form of clomifene with the triphenylethylene structure in red.

Figure 8: Chemical structure of toremifene

Figure 9: Raloxifene has a benzothiophene group (red) and is connected with a flexible carbonyl hinge to a phenyl 4-piperidinoethoxy side chain (green).

Figure 10: Chemical structure of nafoxidine with the dihydronapthalene group in red.

Figure 11: Chemical structure of lasofoxifene shows cis-oriented phenyls.

Figure 12: Bazedoxifene includes an indole system (red) which is connected to an amine through a benzyloxyethyl chain (green).

Figure 13: Chemical structure of ospemifene. Ethoxy side chain ends with a hydroxy group (red) instead of a dimethylamino group as with first-generation SERMs.

Figure 14: The ABCD steroid ring system in 17β-estradiol.

Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonist–antagonist of the estrogen receptor (ER).

- Raloxifene

Raloxifene is used for prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis.

- Selective estrogen receptor modulator

Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

- Estrogen receptor alpha

Two different subtypes of ER have been identified, ERα and ERβ.

- Selective estrogen receptor modulator

Its affinity (Kd) for the ERα is approximately 50 pM, which is similar to that of estradiol.

- Raloxifene

5 related topics with Alpha

Tamoxifen

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Crystallographic structure of afimoxifene (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (ERα) (cyan ribbon).

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men.

In 2006, the large STAR clinical study concluded that raloxifene is also effective in reducing the incidence of breast cancer.

Per one study, tamoxifen had 7% and 6% of the affinity of estradiol for the ERα and ERβ, respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively.

A dimer of the ligand-binding region of ERβ (PDB rendering based on ).

Estrogen receptor

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Estrogen receptors (ERs) are a group of proteins found inside cells.

The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

A dimer of the ligand-binding region of ERα (PDB rendering based on ).

Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs) (GPER (GPR30), ER-X, and Gq-mER), which are mostly G protein-coupled receptors.

Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

Antiestrogen

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Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body.

Antiestrogens include selective estrogen receptor modulators (SERMs) like tamoxifen, clomifene, and raloxifene, the ER silent antagonist and selective estrogen receptor degrader (SERD) fulvestrant, aromatase inhibitors (AIs) like anastrozole, and antigonadotropins including androgens/anabolic steroids, progestogens, and GnRH analogues.

Antiestrogens act as antagonists of the estrogen receptors, ERα and ERβ.

Clomifene

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Medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome.

Clomifene is in the selective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication.

It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifen or raloxifene for this indication.

Clomifene activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels.

Estrogen receptor beta

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One of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen.

Upon binding to 17-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with estrogen receptor α that interact with specific DNA sequences to activate transcription.

Selective estrogen receptor modulators (e.g., tamoxifen, raloxifene)