Editing Selective estrogen receptor modulator (section)

=== Pharmacodynamics ===

SERMs are competitive partial agonists of the ER.<ref name="CameronCameron2013">{{cite book | first1 = John L. | last1 = Cameron | first2 = Andrew M | last2 = Cameron | name-list-style = vanc | title = Current Surgical Therapy | url = https://books.google.com/books?id=QwYyAgAAQBAJ&pg=PA582|date=20 November 2013|publisher=Elsevier Health Sciences|isbn=978-0-323-22511-3|pages=582–}}</ref> Different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so SERMs produce estrogenic or [[antiestrogen]]ic effects depending on the tissue in question, as well as the percentage of [[intrinsic activity]] (IA) of the SERM.<ref name="Huang_Aslanian_2012">{{cite book | first1 = Xianhai | last1 = Huang | first2 = Robert G. | last2 = Aslanian | name-list-style = vanc | title = Case Studies in Modern Drug Discovery and Development|url=https://books.google.com/books?id=MvsSTJigQcMC&pg=PA392|date=19 April 2012|publisher=John Wiley & Sons|isbn=978-1-118-21967-6|pages=392–394}}</ref> An example of a SERM with high IA and thus mostly estrogenic effects is [[chlorotrianisene]], while an example of a SERM with low IA and thus mostly antiestrogenic effects is [[ethamoxytriphetol]]. SERMs like [[clomifene]] and [[tamoxifen]] are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity. [[Raloxifene]] is a SERM 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.<ref name="Huang_Aslanian_2012" />

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

==== Binding site ====
{{See also|Estrogen receptor}}
[[Image:Er domains.svg| thumb| 400px|class=skin-invert-image|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.]]

SERM act on the estrogen receptor (ER), which is an [[intracellular]], ligand-dependent [[transcriptional activator]] and belongs to the [[nuclear receptor]] family.<ref name="Kremoser_2007">{{cite journal | vauthors = Kremoser C, Albers M, Burris TP, Deuschle U, Koegl M | title = Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators | journal = Drug Discovery Today | volume = 12 | issue = 19–20 | pages = 860–9 | date = Oct 2007 | pmid = 17933688 | doi = 10.1016/j.drudis.2007.07.025 }}</ref> Two different subtypes of ER have been identified, [[Estrogen receptor alpha|ERα]] and [[Estrogen receptor beta|ERβ]]. ERα is considered the main medium where estrogen signals are [[Transduction (genetics)|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.<ref name="Rosano_2011"/> ERα and ERβ concentration are known to be different in tissues during development, aging or disease state.<ref name="Nilsson_2011">{{cite journal | vauthors = Nilsson S, Koehler KF, Gustafsson JÅ | title = Development of subtype-selective oestrogen receptor-based therapeutics | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 10 | pages = 778–92 | date = Oct 2011 | pmid = 21921919 | doi = 10.1038/nrd3551 | s2cid = 23043739 }}</ref> Many characteristics are similar between these two types such as size (~600 and 530 [[amino acid]]s) 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]].<ref name="Kremoser_2007" /><ref name="Nilsson_2011" /> The main difference of the ligand-binding domains is determined by [[Leucine|Leu]]-384 and [[Methionine|Met]]-421 in ERα, which are replaced by Met-336 and [[Isoleucine|Ile]]-373, respectively, in ERβ.<ref name="Koehler_2005">{{cite journal | vauthors = Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA | title = Reflections on the discovery and significance of estrogen receptor beta | journal = Endocrine Reviews | volume = 26 | issue = 3 | pages = 465–78 | date = May 2005 | pmid = 15857973 | doi = 10.1210/er.2004-0027 | doi-access = free }}</ref> The variation is greater on the N-terminus between ERα and ERβ.<ref name="Duterte_2000">{{cite journal | vauthors = Dutertre M, Smith CL | title = Molecular mechanisms of selective estrogen receptor modulator (SERM) action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 295 | issue = 2 | pages = 431–7 | date = Nov 2000 | doi = 10.1016/S0022-3565(24)38923-2 | pmid = 11046073 | url = http://jpet.aspetjournals.org/content/295/2/431.short | url-access = subscription }}</ref>

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 [[Dimer (chemistry)|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 [[cysteine]]s and allow for a tetrahedral coordination of two [[zinc]] ions. This coordination makes the binding of ER to estrogen response elements possible.<ref name="Rosano_2011" /> The ligand-binding domain is a globular, three-layered structure made of 11 [[helix]]es and contains a pocket for the natural or synthetic ligand.<ref name="Rosano_2011" /><ref name="Kremoser_2007" /> Influencing factors for binding affinity are mainly the presence of a [[phenol]] moiety, molecular size and shape, double bonds and [[hydrophobicity]].<ref name="Xu_2010">{{cite journal | vauthors = Xu X, Yang W, Li Y, Wang Y | title = Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts | journal = Expert Opinion on Drug Discovery | volume = 5 | issue = 1 | pages = 21–31 | date = Jan 2010 | pmid = 22823969 | doi = 10.1517/17460440903490395 | s2cid = 207492889 }}</ref>

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 [[Coactivator (genetics)|coactivators]] with the [[Consensus sequence|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 [[corepressor]]s NCoR1 or SMRT. In addition, some [[Cofactors and coenzymes|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 [[Coactivator (genetics)|coactivators]] but an ER antagonist in tissues rich in [[Co-repressor|corepressors]].<ref name="Kremoser_2007" />