SELECTIVE ESTROGEN RECEPTOR MODULATORS; ROLE OF SIDE CHAIN IN ACTIVITY MODULATION
Selective estrogen receptor modulators (SERMs) are a class of molecules that activate estrogen receptors (ER), impacting differently on different
tissues. Upon binding to ER, the ligand-receptor complex may present various conformations due to the presence of two different kinds of ERs. Few
of these ligands show estrogenic effects, whereas others will inhibit the action of estrogens. Researchers are working in the direction to generate
the SERMs that have a desirable estrogen-like effects on the various sites i.e., bones, improving lipid profile, reduce hot flushes, but do not act like
estrogens in unwanted ways i.e., causing breast cancer, uterine endometrial proliferation. Given the comprehensive nature of this article, it is not our
intention to revisit many of the issues relating to SERMs, which have already been covered in detail. Rather this article focuses on the aspect that
ligand-mediated structural perturbations in and around the ligand binding pocket, contributed by the side chain effects lead to receptor antagonism.
Adjusting the balance of these effects may provide a novel strategy for designing of improved SERMs. In the light of this, the article will provide an
overview of the SERMs and their structural diversity.
Keywords: Ligand and estrogen receptor, Side chain of selective estrogen receptor modulators, Selective estrogen receptor modulators, Mechanism
Grese TA, Dodge JA Selective estrogen receptor modulators(SERMs) Curr Pharmacol Design [1998; 4: 71-92
Mc Donnell DP molecular pharmacology of SERMs Trends Endocrinol Metab1999: 10: 301-311
Riggs BL, Hartmann LC Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice. N Engl J Med2003; 348 (7): 618â€“29.
Cosman F, Lindsay R. Selective estrogen receptor modulators: clinical spectrum. Endocr Rev 1999; 20:418.
Chaki O. [Next generation selective estrogen receptor modulators]. Clin Calcium 2006; 16:145.
Osborne CK, Zhao H, Fuqua SA: Selective estrogen receptor modulators: Structure, function, and clinical use. J Clin Oncol2000; 18:3172-3186
Goldstein SR: Selective estrogen receptor modulators: A new category of therapeutic agents for extending the health of postmenopausal women. Am J Obstet Gynecol 1998; 179:1479-1484
Fuqua SA, Russo J, Shackney SE, et al: Estrogen, estrogen receptors and selective estrogen receptor modulators in human breast cancer. J Womens Cancer2000;2:21-32
ensen EV, Jordan VC: The estrogen receptor: A model for molecular medicine. Clin Cancer Res 2003; 9:1980-1989
MacGregor JI, Jordan VC: Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev1998;50:151-196
Frasor J, Stossi F, Danes JM, et al: Selective estrogen receptor modulators: Discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res 2004; 64:1522-1533
Bord S, Horner A, Beavan S, et al: Estrogen receptors alpha and beta are differentially expressed in developing human bone. J Clin Endocrinol Metab2001; 86:2309-2314
Kuiper GG, Carlsson B, Grandien K, et al: Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.Endocrinology138:863-870, 1997
Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003; 361:296-300
(a] Katzenellenbogen JA, O'Malley BW, Katzenellenbogen BS: Tripartite steroid hormone receptor pharmacology: Interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol Endocrinol1996; 10:119-131
b] Paech K, Webb P, Kuiper GG, et al: Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 1997; 77:1508-1510
Brzozowski AM, Pike AC, Dauter Z, et al: Molecular basis of agonism and antagonism in the oestrogen receptor. Nature1997; 389:753-758
Ashley C.W. Pike. Lessons learnt from structural studies of the oestrogen receptor. Best Practice & Research Clinical Endocrinology & Metabolism, Vol. 20, No. 1, pp. 1â€“14, 2006
Walker M.P., Zhang M., Le T. P., Wu P., Laine, M., Greene G. L.RAC 3 Is a pro migratory co-activator of ER alpha. Oncogene 2011; 30: 1984-94
Barkhem, T., Nilsson, S. & Gustafsson, J. A. Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action. Am. J. Pharmacogenomics 2004; 4: 19â€“28
Shang, Y. & Brown, M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295: 2465â€“2468
Shiau, A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998; 95: 927â€“937
Jordan, V. C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. Receptor interactions. J. Med. Chem. 46, 883â€“908
Bryant HU, Glasebrook AL, Yang NN, Sato M. A pharmacologic review of raloxifene. J Bone Miner Metab. 1996;14:1â€“9.
Mechanisms of estrogenreceptor signaling: convergence of genomic andnongenomic actions on target genes. Mol. Endocrinol2005; 19: 833â€“842
Simoncini, T. et al. Genomic and nongenomicmechanisms of nitric oxide synthesis induction inhuman endothelial cells by a fourth-generationselective estrogen receptor modulator. Endocrinology2002; 143: 2052â€“2061
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