Pharmacodynamics<unk> s are competitive partial agonists of the ER. Different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so<unk> s produce estrogenic or antiestrogenic effects depending on the specific tissue in question as well as the percentage of intrinsic activity (IA) of the<unk> . An example of a<unk>  with high IA and thus mostly estrogenic effects is chlorotrianisene, while an example of a<unk>  with low IA and thus mostly antiestrogenic effects is ethamoxytriphetol.<unk> s like clomifene and tamoxifen are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity. Raloxifene is a<unk>  that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the uterus while tamoxifen is estrogenic in this part of the body. Binding site Figure 3: The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.<unk>  act on the estrogen receptor (ER), which is an intracellular, ligand-dependent transcriptional activator and belongs to the nuclear receptor family. Two different subtypes of ER have been identified, ERα and ERβ. ERα is considered the main medium where estrogen signals are transduced at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular endothelial cells, bone, and male prostate tissue. ERα and ERβ concentration are known to be different in tissues during development, aging or disease state. Many characteristics are similar between these two types such as size (~600 and 530 amino acids) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the DNA-binding domain and about 56% in the ligand-binding domain (see figure 3). The main difference of the ligand-binding domains is determined by Leu-384 and Met-421 in ERα, which are replaced by Met-336 and Ile-373, respectively, in ERβ. The variation is greater on the N-terminus between ERα and ERβ. DNA-binding domain consists of two subdomains. One with a proximal box that is involved in DNA recognition while the other contains a distal box responsible for DNA-dependent, DNA-binding domain dimerization. The proximal box sequence is identical between ERα and ERβ, which indicates similar specificity and affinity between the two subgroups. DNA-binding domain's globular proteins contain eight cysteines and allow for a tetrahedral coordination of two zinc ions. This coordination makes the binding of ER to estrogen response elements possible. Ligand-binding domain is a globular, three-layered structure made of 11 helixes and contains a pocket for the natural or synthetic ligand. Influencing factors for binding affinity are mainly the presence of a phenol moiety, molecular size and shape, double bonds and hydrophobicity. The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in coactivators with the canonical sequence LXXLL (where L represents leucine or isoleucine and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the corepressors NCoR1 or SMRT. In addition, some cofactors bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in coactivators but an ER antagonist in tissues rich in corepressors. Mechanism of action 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. Estrogenic compounds span a spectrum of activity ranging from: * Full agonists (agonistic in all tissues) such as the natural endogenous hormone estradiol * Mixed agonists/antagonistics (agonistic in some tissues while antagonistic in others) such as tamoxifen (a<unk> . * Pure antagonists (antagonistic in all tissues) such as fulvestrant.<unk> s are known to stimulate estrogenic actions in tissues such as the liver, bone and cardiovascular system but known to block estrogen action where stimulation is not desirable, such as in the breast and the uterus. This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes.<unk> s interact with receptors by diffusing into cells and there binding to ERα or ERβ subunits, which results in dimerization and structural changes of the receptors. This makes it easier for the<unk> s to interact with estrogen response elements which leads to the activation of estrogen-inducible genes and mediating the estrogen effects.<unk> s unique feature is their tissue- and cell-selective activity. There is growing evidence to support that<unk>  activity is mainly determined by selective recruitment of corepressors and coactivators to ER target genes in specific types of tissues and cells.<unk> s can impact coactivator protein stability and can also regulate coactivator activity through post-translational modifications such as phosphorylation. Multiple growth signaling pathways, such as HER2, PKC, PI3K and more, are downregulated in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by activated kinases that also enhance its coactivator activity, affect cell growth and ultimately contribute to drug resistance. The ratio of ERα and ERβ at a target site may be another way<unk>  activity is determined. High levels of cellular proliferation correlate well with a high ERα:ERβ ratio, but repression of cellular proliferation correlates to ERβ being dominant over ERα. The ratio of ERs in neoplastic and normal breast tissue could be important when considering chemoprevention with<unk> s. When looking at the differences between ERα and ERβ, Activating Function 1 (AF-1) and AF-2 are important. Together they play an important part in the interaction with other co-regulatory proteins that control gene transcription. AF-1 is located in the amino terminus of the ER and is only 20% homologous in ERα and ERβ. On the other hand, AF-2 is very similar in ERα and ERβ, and only one amino acid is different. Studies have shown that by switching AF-1 regions in ERα and ERβ, that there are specific differences in transcription activity. Generally,<unk> s can partially activate engineered genes through ERα by an estrogen receptor element, but not through ERβ. Although, raloxifene and the active form of tamoxifen can stimulate AF-1-regulated reporter genes in both ERα and ERβ. Because of the discovery that there are two ER subtypes, it has brought about the synthesis of a range of receptor specific ligands that can switch on or off a particular receptor. However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a<unk> . X-ray crystallography of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site. The main result of a ligand-binding to ER is a structural rearrangement of the ligand-binding pocket, primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a hydrophobic pocket that regulates cofactors and receptor pharmacology. The correct folding of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators (see figure 4). Coactivators are not just protein partners that connect sites together in a complex. Coactivators play an active role in modifying the activity of a complex. Post-translation modification of coactivators can result in a dynamic model of steroid hormone action by way of multiple kinase pathways initiated by cell surface growth factor receptors. Under the guidance of a multitude of protein remodelers to form a multiprotein coactivator complex that can interact with the phosphorylated ER at a specific gene promoter site, the core coactivator first has to recruit a specific set of cocoactivators. The proteins that the core
Selective estrogen receptor modulator
Selective androgen receptor modulator
Selective estrogen receptor degrader
Selective progesterone receptor modulator
Antiestrogen
Antiandrogen
Aromatase inhibitor
Steroidal aromatase inhibitor