Estrogen as Part of Bone Resorption in the Body

Estrogens as Part of Bone Resorption in the Body

Estrogens' (Estriol, Estradiol (most abundant and influential of the estrogens), Estrone) main role in the body is to develop secondary sexual characteristics in females, but the list of estrogen's roles in the body is still growing; recent research has shown that estrogen is part of bone resorption in the body. Estrogens are produced in the gonads and distributed throughout the body in the blood stream. Estrogen works by passing through plasma membranes and binding to receptor proteins found intracellular inside the nucleus of a cell. Once bound a signal transduction is completed when the receptor protein interacts with a hormone response element and begins DNA transcription (induction) resulting in the translation of a protein. Estrogen is also known to have plasma membrane binding receptors that cause vasodilatation which occurs much too fast for simple transcription to take place (Hours or days for transcription opposed to seconds or minutes for blood vasodilatation). There are two species of receptors that estrogen can bind to. The first one, alpha, is typically an activator while the second, beta, can be both an inhibitor to alpha or simply an activator. From these receptors numerous coregulator proteins bind, and begin induction of the signal transduction pathway depending entirely which tissue the hormone was received in. (Riggs et al, 2003)

Hormone replacement treatment with estrogen has recently been attributed to increased risk of stroke, ovarian cancer, endometrial cancer, and cervical cancer (Garnet et al). Selective estrogen-receptor modulators ( SERMs) are believed to have the benefits of hormone replacement treatment by binding to estrogen receptors, but lack the adverse effects of estrogen throughout the body (Riggs et al, 2003).

SERMs can be antagonistic or agonistic relative to estrogen depending which receptor they are binding to in the body . If a molecule has a great affinity to bind to a receptor it is considered antagonistic to a hormone with a lower affinity for that same binding site. Tamoxifene is an antagonist to estrogen, which is why it is effective in breast cancer treatments. It acts on the binding site but does not start gene transcription like estrogen does (Biochemistry, 2009).

SERMs have many medicinal uses without the harmful effects that have been recently found to be associated with hormone therapy. Currently the list of SERMs includes: Tamoxifen, Toremifene, Raloxifene and Bazedoxifene, and they are used in women for oral contraception, hormone replacement therapy, menopausal therapy and postmenopausal complications like: reduced menopausal vasomotor symptoms, vaginal atrophy, and helps prevent fractures. In men SERMs are used in the treatment of prostate cancer, osteoporosis, secondary hypogonadism infertility, and diabetes (Pickar et al, 2010). A novel SERM could affect anyone of these treatments for estrogen receptors. A greater affinity for binding to receptors could lead to the SERM being part of a hormone replacement therapy and antagonising estrogen’s adverse effects on the body. The actual pharmaceutical significance can only be determined after testing is done, but this work will open a wide range of possibilities for the discovery of a more efficient SERM then all ready exists.

Objective:
1) Synthesising 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)ethoxy)benzoyl.
2) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to NMe2.
3) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to NEt2.
4) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to NPr2.
5) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to NiPr2.
6) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to 1-pyrrolidinyl.
7) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to 1-piperidinyl.
8) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to 1-morpholinyl
9) Terminally binding 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzyl and 4-(2-(N,N-Dialkyl-amino)chloroethoxy)benzoyl to 1-homopoperidinyl.

Proposed Methodology:
With the aim of synthesising a precursor compound of a SERM the methodology will be an adapted from a letter published in 2005 by Ji et al. The 4-hydroxybenzalhyde(NAME) and 1,2 dibromoethane reacted with a metal catalyst and supporting ligands will produce (NAME). The molecule is reduced NaBH4 methanol at room temperature producing an alcohol (NAME). These compounds will be reacted with amines NMe2, NEt2, NPr2, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, and 1-homopoperidinyl; along with NiPr2. A solution of one compound will be obtained in THF and cooled to 0oC and gaseous HCl bubbled through until no more thickening was observed, then SOCl2 was added and the mixture will be heated at 50oC until the mixture becomes clear. The reaction mixture will be cooled and the desired compounds should be present.

Anticipated Significance:
The compounds developed here will lead to novel SERMs with diverse affinity for estrogen receptors. A greater affinity for binding to receptors could lead to the SERM being part of hormone replacement therapy and antagonising estrogen’s bad effects on the body. The actual pharmaceutical significance will need to be determined at a later date, but this work will open a wide range of possibilities for the discovery of a more efficient SERM then all ready exists.

Literature Cited:
Riggs BL, Hartmann LC (2003). "Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice". N Engl J Med 348 (7): 618–29.
http://proquest.umi.com/pqdweb?index=0&sid=2&srchmode=1&vinst=PROD&fmt=3...

Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures: The Women's Health Initiative Randomized Trial
Garnet L. Anderson; Howard L. Judd; Andrew M. Kaunitz; David H. Barad; Shirley A. A. Beresford; Mary Pettinger; James Liu; S. Gene McNeeley; Ana Maria Lopez
JAMA. 2003;290:1739-1748.
http://jama.ama-assn.org/cgi/content/full/290/13/1739

Falahati-Nini A, Riggs BL, Atkinson EJ, O’FallonWM, Eastell R, Khosla S. Rela-tive contributions of testosterone and estrogen in regulating bone resorptionand formation in normal elderly men. J Clin Invest 2000;106:1553–60.
Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, MichopoulosJ. Effectiveness of combined tamoxifen citrate and testosterone unde-canoate treatment in men with idiopathic oligozoospermia. Fertil Steril2003;80:914–20.

Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermiaDimitrios A Adamopoulos, M.D.Athina Pappa, M.Sc., Evangelia Billa, M.D., Stamatina Nicopoulou, M.D., Eftychia Koukkou, M.D.,John Michopoulos, M.D.Received 13 November 2002; received in revised form 16 April 2003; accepted 16 April 2003.

Minireview: Rapid Actions of Sex Steroids in the EndotheliumRenee W. Y. Chow, David J. Handelsman and Martin K. C. NgHeart Research Institute (R.W.Y.C., M.K.C.N.), Sydney, New South Wales 2042, Australia; ANZAC Research Institute (D.J.H.), Sydney, New South Wales 2139 Australia; and Sydney Medical School (D.J.H., M.K.C.N.), New South Wales 2006, University of Sydney, AustraliaEndocrinology Vol. 151, No. 6 2411-2422
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