Estradiol
From DrugPedia: A Wikipedia for Drug discovery
Estradiol (17β-estradiol) (also oestradiol) is a sex hormone. Mislabelled the "female" hormone, it is also present in males; it represents the major estrogen in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure.
Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
Production
During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovary|ovaries by the aromatization of androstenedione (produced in the theca folliculi cells} to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid reductase. Smaller amounts of estradiol are also produced by the adrenal cortex, and in me), by the testes. Estradiol is not only produced in the gonads: in both sexes, precursor hormones, specifically testosterone, are converted by aromatization to estradiol. In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial walls.
Mechanism of action
Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell.
Estradiol binds well to both estrogen receptors, ERα and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulators, or SERMs.
Estradiol is the most potent naturally-occurring estrogen.
Recently there has been speculation about a membrane estrogen receptor, ERX.
PUBCHEM (5757)
Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
Therapeutic Indications
- Menopause
- Osteoporosis
KEGG Database(C00951,D00105) Pathway Androgen and estrogen metabolism Prostate cancer
NEXT BIO Database
Drug Type: Small Molecule; Approved; Investigational
Pharmacology: Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level.
Mechanism of Action: Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Indication: For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).
Half Life: 36 hours
| MMDB ID | PDB ID | Reference |
|---|---|---|
| 14139 | 1QKT | Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065 |
| 14140 | 1QKU | Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065 |
| 17807 | 1JGL | Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694 |
| 18390 | 1G50 | Eiler S, Gangloff M, Duclaud S, Moras D, Ruff MOverexpression, purification, and crystal structure of native ER alpha LBDProtein Expr. Purif. v22, p.165-173 |
| 18412 | 1JNN | Monnet C, Bettsworth F, Stura EA, Le Du MH, Menez R, Derrien L, Zinn-Justin S, Gilquin B, Sibai G, Battail-Poirot N, Jolivet M, Menez A, Arnaud M, Ducancel F, Charbonnier JBHighly specific anti-estradiol antibodies: structural characterisation and binding diversityJ. Mol. Biol. v315, p.699-712 |
| 20338 | 1GWR | Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike ACInteraction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alphaJ. Biol. Chem. v277, p.21862-21868 |
| 20905 | 1LHU | Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YASteroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformationJ. Biol. Chem. v277, p.32086-32093 |
| 25056 | 1PCG | Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AFHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactionsProc. Natl. Acad. Sci. U. S. A. v100, p.11273-11278 |
| 35805 | 2D06 | Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JLThe structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substratesJ. Biol. Chem. v280, p.41482-41486 |
| 43057 | 2J7X | Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5.
Pike ACW, Brzozowski AM, Hubbard RE, Walton J, Bonn T, - A, Thorsell G, Engstrom O, Ljunggren J, Gustaffson J-A, Carlquist M, 2006/10/17 |
| 47760 | 1A52 | Tanenbaum DM, Wang Y, Williams SP, Sigler PBCrystallographic comparison of the estrogen and progesterone receptor's ligand binding domainsProc. Natl. Acad. Sci. U. S. A. v95, p.5998-6003 |
| 47957 | 1AQU | Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908 |
| 49701 | 1IOL | Azzi A, Rehse PH, Zhu DW, Campbell RL, Labrie F, Lin SXCrystal structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase complexed with 17 beta-estradiolNat. Struct. Biol. v3, p.665-668 |
| 55024 | 1A27 | Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152 |
| 56114 | 1FDS | Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915 |
| 56115 | 1FDT | Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915 |
| 56116 | 1FDW | Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152 |
| 60515 | 2OCF | Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20 |
| 8897 | 1ERE | Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist MMolecular basis of agonism and antagonism in the oestrogen receptorNature v389, p.753-758 |
| Physical Property | Value | Units | Temp (deg C) | Source |
|---|---|---|---|---|
| Melting Point | 178.5 | deg C | EXP | |
| log P (octanol-water) | 4.01 (none) | EXP | ||
| Water Solubility | 3.6 | mg/L | 27 | EXP |
| Vapor Pressure | 1.26E-08 | mm Hg | 25 | EST |
| Henry's Law Constant | 3.64E-11 | atm-m3/mole | 25 | EST |
| Atmospheric OH Rate Constant | 1.23E-10 | cm3/molecule-sec | 25 | EST |
| Organism | Test Type | Route | Reported Dose (Normalized Dose) | Effect | Source |
|---|---|---|---|---|---|
| rat | LD | subcutaneous | > 300mg/kg (300mg/kg) | Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995. |
Lipinski’s “Rule of Five” Prediction for a Compound’s ABSORPTION OR PERMEABILITY PROPERTIES
| 4 | 3 | 2 | 1 | 0 |
|---|---|---|---|---|
| GOOD | INDETERMINATE | INDETERMINATE | INDETERMINATE | POOR |
Reference Article Ref1 Virtual and biomolecular screening converge on a selective agonist for GPR30
Cristian G Bologa1,7, Chetana M Revankar2,3,7, Susan M Young3, Bruce S Edwards3,4, Jeffrey B Arterburn5, Alexander S Kiselyov6, Matthew A Parker6, Sergey E Tkachenko6, Nikolay P Savchuck6, Larry A Sklar3,4, Tudor I Oprea1 & Eric R Prossnitz2,3
Estrogen is a hormone critical in the development, normal physiology and pathophysiology1 of numerous human tissues2. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand–activated family of transcription factors3. We have recently shown that the seven-transmembrane G protein–coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways4. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
Ref2 Drugs Fut 2006, 31(1): 65 ISSN 0377-8282 Copyright 2006 Prous Science CCC: 0377-8282 DOI: 10.1358/dof.2006.031.01.959122
Structure-function similarity between vitamin D3 and estrogens: Scope for effective drug design for vitamin D3 and estrogen dependent disorders Ray, S., Gupta, A.
Vitamin D3 and estradiol are essential hormones that are formed in the body from the same source cholesterol. Whereas vitamin D3 is required mainly for calcium regulation and bone formation, estradiol regulates the reproductive cycle in women and maintains female characteristics. Both hormones are involved in various other functions in the body and act through their respective receptors which belong to the nuclear receptor superfamily. This article discusses the major role of vitamin D3 and estradiol in disorders such as osteoporosis, cancer and calcium regulation. Their functional similarity may be due to their participation at different junctures of the same mechanistic pathway or else a crosstalk between the two hormones and their opposite receptors. This suggests the possibility of designing effective drugs that would interact with both vitamin D3 and estrogen receptors for the treatment of vitamin D3 and estrogen-dependent disorders.
