Editing Serotonin transporter (section)

==Pharmacology==

In 1995 and 1996, scientists in Europe had identified the polymorphism [[5-HTTLPR]], a serotonin-transporter in the gene ''[[SLC6A4]]''.<ref>{{cite journal | vauthors = Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP | title = Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene | journal = Journal of Neural Transmission. General Section | volume = 102 | issue = 3 | pages = 247–254 | year = 1995 | pmid = 8788073 | doi = 10.1007/BF01281159 | author8-link = K. P. Lesch | s2cid = 8474414 | author7-link = P. Riederer }}</ref><ref>{{cite journal | vauthors = Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP | title = Allelic variation of human serotonin transporter gene expression | journal = Journal of Neurochemistry | volume = 66 | issue = 6 | pages = 2621–2624 | date = June 1996 | pmid = 8632190 | doi = 10.1046/j.1471-4159.1996.66062621.x | s2cid = 42037860 | author7-link = Klaus-Peter Lesch | author5-link = P. Riederer }}</ref> In December 1996, a group of researchers led by D.A. Collier of the [[Institute of Psychiatry, Psychology and Neuroscience]], published their findings in ''Molecular Psychiatry'', that, "[[5-HTTLPR]]-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders."<ref>{{cite journal | vauthors = Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Müller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP | title = A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders | journal = Molecular Psychiatry | volume = 1 | issue = 6 | pages = 453–460 | date = December 1996 | pmid = 9154246 }}</ref>

SERT spans the plasma membrane 12&nbsp;times. It belongs to the NE, DA, SERT monoamine transporter family. Transporters are important sites for agents that treat [[psychiatric disorder]]s. Drugs that reduce the binding of serotonin to transporters ([[serotonin reuptake inhibitor]]s, or SRIs) are used to treat mental disorders. The [[selective serotonin reuptake inhibitor]] (SSRI) [[fluoxetine]] and the [[tricyclic antidepressant]] (TCA) [[clomipramine]] are examples of serotonin reuptake inhibitors.

Following the elucidation of structures of the homologous bacterial transporter, LeuT, co-crystallized with [[tricyclic antidepressants]] in the vestibule leading from the extracellular space to the central substrate site it was inferred that this binding site did also represent the binding site relevant for antidepressant binding in SERT.<ref>{{cite journal | vauthors = Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN | title = LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake | journal = Science | volume = 317 | issue = 5843 | pages = 1390–1393 | date = September 2007 | pmid = 17690258 | pmc = 3711652 | doi = 10.1126/science.1147614 | bibcode = 2007Sci...317.1390Z }}</ref> However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhibitors bind to the central binding site overlapping the substrate binding site.<ref>{{cite journal | vauthors = Sinning S, Musgaard M, Jensen M, Severinsen K, Celik L, Koldsø H, Meyer T, Bols M, Jensen HH, Schiøtt B, Wiborg O | title = Binding and orientation of tricyclic antidepressants within the central substrate site of the human serotonin transporter | journal = The Journal of Biological Chemistry | volume = 285 | issue = 11 | pages = 8363–8374 | date = March 2010 | pmid = 19948720 | pmc = 2832986 | doi = 10.1074/jbc.M109.045401 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Andersen J, Taboureau O, Hansen KB, Olsen L, Egebjerg J, Strømgaard K, Kristensen AS | title = Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants | journal = The Journal of Biological Chemistry | volume = 284 | issue = 15 | pages = 10276–10284 | date = April 2009 | pmid = 19213730 | pmc = 2665081 | doi = 10.1074/jbc.M806907200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Koldsø H, Severinsen K, Tran TT, Celik L, Jensen HH, Wiborg O, Schiøtt B, Sinning S | title = The two enantiomers of citalopram bind to the human serotonin transporter in reversed orientations | journal = Journal of the American Chemical Society | volume = 132 | issue = 4 | pages = 1311–1322 | date = February 2010 | pmid = 20055463 | doi = 10.1021/ja906923j | bibcode = 2010JAChS.132.1311K }}</ref> The ''Drosophila'' dopamine transporter, which displays a pharmacology similar to SERT, was crystallized with tricyclic antidepressants and confirmed the earlier finding that the substrate binding site is also the antidepressant binding site.<ref>{{cite journal | vauthors = Penmatsa A, Wang KH, Gouaux E | title = X-ray structure of dopamine transporter elucidates antidepressant mechanism | journal = Nature | volume = 503 | issue = 7474 | pages = 85–90 | date = November 2013 | pmid = 24037379 | pmc = 3904663 | doi = 10.1038/nature12533 | bibcode = 2013Natur.503...85P }}</ref>

[[File:Mattson 2005.svg|thumb|177px|'''12a''']] {{stack|[[File:Tamagnan 2005.svg|thumb|190px|'''4b''']]}}

===Ligands===
* [[DASB]]
* compound 4b: ''K''i = 17 pM; 710-fold and 11,100-fold selective over DAT and NET<ref name="pmid15686927">{{cite journal | vauthors = Tamagnan G, Alagille D, Fu X, Kula NS, Baldessarini RJ, Innis RB, Baldwin RM | title = Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 4 | pages = 1131–1133 | date = February 2005 | pmid = 15686927 | doi = 10.1016/j.bmcl.2004.12.014 }}</ref>
* compound (+)-12a: ''K''i = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT<sub>1A</sub>, and 5-HT<sub>6</sub>.<ref name="pmid16162005">{{cite journal | vauthors = Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ | title = Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 19 | pages = 6023–6034 | date = September 2005 | pmid = 16162005 | doi = 10.1021/jm0503291 }}</ref> [[Bioisostere|Isostere]]s<ref name="pmid17766113">{{cite journal | vauthors = Dalton King H, Denhart DJ, Deskus JA, Ditta JL, Epperson JR, Higgins MA, Kung JE, Marcin LR, Sloan CP, Mattson GK, Molski TF, Krause RG, Bertekap RL, Lodge NJ, Mattson RJ, Macor JE | title = Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 20 | pages = 5647–5651 | date = October 2007 | pmid = 17766113 | doi = 10.1016/j.bmcl.2007.07.083 }}</ref>
* 3-''cis''-(3-Aminocyclopentyl)indole 8a: ''K''i = 220 pM<ref>{{cite journal | vauthors = King HD, Meng Z, Deskus JA, Sloan CP, Gao Q, Beno BR, Kozlowski ES, Lapaglia MA, Mattson GK, Molski TF, Taber MT, Lodge NJ, Mattson RJ, Macor JE | title = Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 21 | pages = 7564–7572 | date = November 2010 | pmid = 20949929 | doi = 10.1021/jm100515z }}</ref>
* allosteric modulator: 3′-Methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5′(4′H)-isoxazole} (compound 7a)<ref>{{cite journal | vauthors = Dallanoce C, Canovi M, Matera C, Mennini T, De Amici M, Gobbi M, De Micheli C | title = A novel spirocyclic tropanyl-Δ²-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake | journal = Bioorganic & Medicinal Chemistry | volume = 20 | issue = 21 | pages = 6344–6355 | date = November 2012 | pmid = 23022052 | doi = 10.1016/j.bmc.2012.09.004 }}</ref>
* allosteric modulator: ''p''-Trifluoromethyl-[[methcathinone]]<ref name="pmid31028773">{{cite journal | vauthors = Niello M, Cintulova D, Hellsberg E, Jäntsch K, Holy M, Ayatollahi LH, Cozzi NV, Freissmuth M, Sandtner W, Ecker GF, Mihovilovic MD, Sitte HH | title = para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter | journal = Neuropharmacology | volume = 161 | pages = 107615 | date = December 2019 | pmid = 31028773 | doi = 10.1016/j.neuropharm.2019.04.021 | s2cid = 128363044 | doi-access =  }}</ref>