View source for 5-HT6 receptor

{{DISPLAYTITLE:5-HT<sub>6</sub> receptor}}
{{PBB|geneid=3362}}

The '''5-HT<sub>6</sub> receptor''' is a subtype of [[5-HT receptor]] that binds the [[endogenous]] [[neurotransmitter]] [[serotonin]] (5-hydroxytryptamine, 5-HT).<ref name="pmid8522988">{{cite journal | author = Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW | title = Cloning, characterization, and chromosomal localization of a human 5-HT<sub>6</sub> serotonin receptor | journal = J. Neurochem. | volume = 66 | issue = 1 | pages = 47–56 | year = 1996 | pmid = 8522988 | doi = 10.1046/j.1471-4159.1996.66010047.x }}</ref> It is a [[G protein-coupled receptor]] (GPCR) that is coupled to [[G(s)alpha|G<sub>s</sub>/G<sub>o</sub>]] and mediates [[EPSP|excitatory]] [[neurotransmission]].<ref name="pmid8522988">{{cite journal | author = Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW | title = Cloning, characterization, and chromosomal localization of a human 5-HT<sub>6</sub> serotonin receptor | journal = J. Neurochem. | volume = 66 | issue = 1 | pages = 47–56 | year = 1996 | pmid = 8522988 | doi = 10.1046/j.1471-4159.1996.66010047.x }}</ref> ''HTR6'' denotes the [[human]] [[gene]] encoding for the [[Receptor (biochemistry)|receptor]].<ref name="entrez">{{cite web | title = Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3362| accessdate = }}</ref>

== Distribution ==

The 5-HT<sub>6</sub> receptor is expressed almost exclusively in the [[brain]].<ref name="pmid14965245">{{cite journal | author = Woolley ML, Marsden CA, Fone KC | title = 5-ht6 receptors | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 3 | issue = 1 | pages = 59–79 | year = 2004 | month = February | pmid = 14965245 | doi = 10.2174/1568007043482561| url = }}</ref> It is distributed in various areas including, but not limited to, the [[olfactory tubercle]], [[cerebral cortex]] ([[frontal cortex|frontal]] and [[Entorhinal cortex|entorhinal]] regions), [[nucleus accumbens]], [[striatum]], [[caudate nucleus]], [[hippocampus]], and the molecular layer of the [[cerebellum]].<ref name="pmid8389146">{{cite journal | author = Ruat M, Traiffort E, Arrang JM, ''et al.'' | title = A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation | journal = Biochemical and Biophysical Research Communications | volume = 193 | issue = 1 | pages = 268–76 | year = 1993 | month = May | pmid = 8389146 | doi = 10.1006/bbrc.1993.1619| url = http://linkinghub.elsevier.com/retrieve/pii/S0006291X83716190}}</ref><ref name="pmid9037500">{{cite journal | author = Gérard C, Martres MP, Lefèvre K, ''et al.'' | title = Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system | journal = Brain Research | volume = 746 | issue = 1-2 | pages = 207–19 | year = 1997 | month = January | pmid = 9037500 | doi = 10.1016/S0006-8993(96)01224-3| url = http://linkinghub.elsevier.com/retrieve/pii/S0006-8993(96)01224-3}}</ref><ref name="pmid8522988">{{cite journal | author = Kohen R, Metcalf MA, Khan N, ''et al.'' | title = Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor | journal = Journal of Neurochemistry | volume = 66 | issue = 1 | pages = 47–56 | year = 1996 | month = January | pmid = 8522988 | doi = 10.1046/j.1471-4159.1996.66010047.x| url = http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=1996&volume=66&issue=1&spage=47}}</ref> Based on its abundance in [[extrapyramidal system|extrapyramidal]], [[limbic system|limbic]], and [[cortical]] regions it can be suggested that the 5-HT<sub>6</sub> receptor plays a role in functions like [[motor control]], [[emotionality]], [[cognition]], and [[memory]].<ref name="pmid9037500">{{cite journal | author = Gérard C, Martres MP, Lefèvre K, ''et al.'' | title = Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system | journal = Brain Research | volume = 746 | issue = 1-2 | pages = 207–19 | year = 1997 | month = January | pmid = 9037500 | doi = 10.1016/S0006-8993(96)01224-3| url = http://linkinghub.elsevier.com/retrieve/pii/S0006-8993(96)01224-3}}</ref><ref name="pmid10432491">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1016/S0893-133X(99)00044-5 | author = Hamon M, Doucet E, Lefèvre K, ''et al.'' | title = Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 21 | issue = 2 Suppl | pages = 68S–76S | year = 1999 | month = August | pmid = 10432491 | doi = 10.1016/S0893-133X(99)00044-5}}</ref><ref name="pmid14965245">{{cite journal | author = Woolley ML, Marsden CA, Fone KC | title = 5-ht6 receptors | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 3 | issue = 1 | pages = 59–79 | year = 2004 | month = February | pmid = 14965245 | doi = 10.2174/1568007043482561| url = }}</ref>

== Function ==

Blockade of central 5-HT<sub>6</sub> receptors has been shown to increase [[glutamatergic]] and [[cholinergic]] neurotransmission in various brain areas,<ref name="pmid10780993">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.bjp.0703288 | author = Dawson LA, Nguyen HQ, Li P | title = In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate | journal = British Journal of Pharmacology | volume = 130 | issue = 1 | pages = 23–6 | year = 2000 | month = May | pmid = 10780993 | pmc = 1572041 | doi = 10.1038/sj.bjp.0703288}}</ref><ref name="pmid11682249">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1016/S0893-133X(01)00265-2 | author = Dawson LA, Nguyen HQ, Li P | title = The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 25 | issue = 5 | pages = 662–8 | year = 2001 | month = November | pmid = 11682249 | doi = 10.1016/S0893-133X(01)00265-2}}</ref><ref name="pmid15223298">{{cite journal | author = King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC | title = 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism | journal = Neuropharmacology | volume = 47 | issue = 2 | pages = 195–204 | year = 2004 | month = August | pmid = 15223298 | doi = 10.1016/j.neuropharm.2004.03.012 | url = http://linkinghub.elsevier.com/retrieve/pii/S0028390804000863}}</ref><ref name="pmid18625457">{{cite journal | author = Upton N, Chuang TT, Hunter AJ, Virley DJ | title = 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease | journal = Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics | volume = 5 | issue = 3 | pages = 458–69 | year = 2008 | month = July | pmid = 18625457 | doi = 10.1016/j.nurt.2008.05.008 | url = http://linkinghub.elsevier.com/retrieve/pii/S1933-7213(08)00100-1}}</ref> whereas activation enhances [[GABAergic]] signaling in a widespread manner.<ref name="pmid17625499">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.npp.1301503 | author = Schechter LE, Lin Q, Smith DL, ''et al.'' | title = Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 33 | issue = 6 | pages = 1323–35 | year = 2008 | month = May | pmid = 17625499 | doi = 10.1038/sj.npp.1301503}}</ref> Antagonism of 5-HT<sub>6</sub> receptors also facilitates [[dopamine]] and [[norepinephrine]] release in the frontal cortex,<ref name="pmid18625457">{{cite journal | author = Upton N, Chuang TT, Hunter AJ, Virley DJ | title = 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease | journal = Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics | volume = 5 | issue = 3 | pages = 458–69 | year = 2008 | month = July | pmid = 18625457 | doi = 10.1016/j.nurt.2008.05.008 | url = http://linkinghub.elsevier.com/retrieve/pii/S1933-7213(08)00100-1}}</ref><ref name="pmid14618683">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1002/syn.10288 | author = Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA | title = 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex | journal = Synapse (New York, N.Y.) | volume = 51 | issue = 2 | pages = 158–64 | year = 2004 | month = February | pmid = 14618683 | doi = 10.1002/syn.10288}}</ref> while stimulation has the opposite effect.<ref name="pmid17625499">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.npp.1301503 | author = Schechter LE, Lin Q, Smith DL, ''et al.'' | title = Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 33 | issue = 6 | pages = 1323–35 | year = 2008 | month = May | pmid = 17625499 | doi = 10.1038/sj.npp.1301503}}</ref>

Despite the 5-HT<sub>6</sub> receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.<ref name="pmid17625499">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.npp.1301503 | author = Schechter LE, Lin Q, Smith DL, ''et al.'' | title = Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 33 | issue = 6 | pages = 1323–35 | year = 2008 | month = May | pmid = 17625499 | doi = 10.1038/sj.npp.1301503}}</ref> In parallel with this, 5-HT<sub>6</sub> antagonists improve cognition, learning, and memory,<ref name="pmid19086256">{{cite journal | author = King MV, Marsden CA, Fone KC | title = A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory | journal = Trends in Pharmacological Sciences | volume = 29 | issue = 9 | pages = 482–92 | year = 2008 | month = September | pmid = 19086256 | doi = 10.1016/j.tips.2008.07.001| url = }}</ref> and agents such as [[latrepirdine]], [[Lu AE58054]], and [[SB-742,457]] are being developed as novel treatments for [[Alzheimer's disease]] and other [[dementia]]s.<ref name="pmid18691131">{{cite journal | author = Geldenhuys WJ, Van der Schyf CJ | title = Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 12 | pages = 1035–48 | year = 2008 | pmid = 18691131 | doi = 10.2174/156802608785161420| url = http://www.bentham-direct.org/pages/content.php?CTMC/2008/00000008/00000012/0004R.SGM}}</ref><ref name="pmid18625457">{{cite journal | author = Upton N, Chuang TT, Hunter AJ, Virley DJ | title = 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease | journal = Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics | volume = 5 | issue = 3 | pages = 458–69 | year = 2008 | month = July | pmid = 18625457 | doi = 10.1016/j.nurt.2008.05.008 | url = http://linkinghub.elsevier.com/retrieve/pii/S1933-7213(08)00100-1}}</ref><ref name="pmid19589055">{{cite journal | author = Geldenhuys WJ, Van der Schyf CJ | title = The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease | journal = Expert Review of Neurotherapeutics | volume = 9 | issue = 7 | pages = 1073–85 | year = 2009 | month = July | pmid = 19589055 | doi = 10.1586/ern.09.51 | url = http://www.future-drugs.com/doi/abs/10.1586/ern.09.51?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov}}</ref> 5-HT<sub>6</sub> antagonists have also been shown to reduce [[appetite]] and produce [[weight loss]], and as a result, [[PRX-07034]], [[BVT-5,182]], and [[BVT-74,316]] are being investigated for the treatment of [[obesity]].<ref name="pmid18068807">{{cite journal | author = Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H | title = Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders | journal = Pharmacology & Therapeutics | volume = 117 | issue = 2 | pages = 207–31 | year = 2008 | month = February | pmid = 18068807 | doi = 10.1016/j.pharmthera.2007.08.006 | url = http://linkinghub.elsevier.com/retrieve/pii/S0163-7258(07)00208-2}}</ref><ref name="pmid18755168">{{cite journal | author = Frassetto A, Zhang J, Lao JZ, ''et al.'' | title = Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor | journal = Brain Research | volume = 1236 | issue = | pages = 140–4 | year = 2008 | month = October | pmid = 18755168 | doi = 10.1016/j.brainres.2008.08.012 | url = http://linkinghub.elsevier.com/retrieve/pii/S0006-8993(08)01987-2}}</ref>

Recently, the 5-HT<sub>6</sub> agonists [[WAY-181,187]] and [[WAY-208,466]] have been demonstrated to be active in rodent models of [[major depression|depression]], [[anxiety]], and [[obsessive-compulsive disorder]] (OCD), and such agents may be useful treatments for these conditions.<ref name="pmid20217056">{{cite journal | author = Carr GV, Schechter LE, Lucki I | title = Antidepressant and anxiolytic effects of selective 5-HT(6) receptor agonists in rats | journal = Psychopharmacology | volume = | issue = | pages = | year = 2010 | month = March | isbn = 0021301017987 | pmid = 20217056 | pmc = 2910165 | doi = 10.1007/s00213-010-1798-7}}</ref><ref name="pmid17625499">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.npp.1301503 | author = Schechter LE, Lin Q, Smith DL, ''et al.'' | title = Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 33 | issue = 6 | pages = 1323–35 | year = 2008 | month = May | pmid = 17625499 | doi = 10.1038/sj.npp.1301503}}</ref> Additionally, it can be inferred that 5-HT<sub>6</sub> activation likely plays a major role in the therapeutic benefits of [[serotonergic]] [[antidepressant]]s like the [[selective serotonin reuptake inhibitor]]s (SSRIs) and [[tricyclic antidepressant]]s (TCAs).

== Ligands ==

A large number of selective 5-HT<sub>6</sub> ligands have now been developed and this is a productive current area of research.<ref name="pmid18793848">{{cite journal | author = Trani G, Baddeley SM, Briggs MA, Chuang TT, Deeks NJ, Johnson CN, Khazragi AA, Mead TL, Medhurst AD, Milner PH, Quinn LP, Ray AM, Rivers DA, Stean TO, Stemp G, Trail BK, Witty DR | title = Tricyclic azepine derivatives as selective brain penetrant 5-HT<sub>6</sub> receptor antagonists | journal = Bioorg. Med. Chem. Lett. | volume = 18 | issue = 20 | pages = 5698–700 | year = 2008 | month = October | pmid = 18793848 | doi = 10.1016/j.bmcl.2008.08.010 | url = | issn = }}</ref><ref name="pmid19152787">{{cite journal | author = Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ | title = Identification of a series of benzoxazoles as potent 5-HT<sub>6</sub> ligands | journal = Bioorg. Med. Chem. Lett. | volume = 19 | issue = 4 | pages = 1115–7 | year = 2009 | month = February | pmid = 19152787 | doi = 10.1016/j.bmcl.2008.12.107 | url = | issn = }}</ref><ref name="pmid15745826">{{cite journal |author=Lee M, Rangisetty JB, Pullagurla MR, ''et al'' |title=1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands |journal=Bioorg. Med. Chem. Lett. |volume=15 |issue=6 |pages=1707–11 |year=2005 |pmid=15745826 |doi=10.1016/j.bmcl.2005.01.031 |url=}}</ref><ref name="pmid16913710">{{cite journal |author=Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA |title=Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors |journal=J. Med. Chem. |volume=49 |issue=17 |pages=5217–25 |year=2006 |pmid=16913710 |doi=10.1021/jm060469q |url=}}</ref><ref name="pmid15713394">{{cite journal |author=Zhou P, Yan Y, Bernotas R, ''et al'' |title=4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands |journal=Bioorg. Med. Chem. Lett. |volume=15 |issue=5 |pages=1393–6 |year=2005 |pmid=15713394 |doi=10.1016/j.bmcl.2005.01.005 |url=}}</ref><ref name="pmid16143522">{{cite journal |author=Ahmed M, Briggs MA, Bromidge SM, ''et al'' |title=Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists |journal=Bioorg. Med. Chem. Lett. |volume=15 |issue=21 |pages=4867–71 |year=2005 |pmid=16143522 |doi=10.1016/j.bmcl.2005.06.107 |url=}}</ref><ref name="pmid18843410">{{cite journal | author = Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R | title = Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT<sub>6</sub> receptor ligands | journal = Org. Biomol. Chem. | volume = 6 | issue = 20 | pages = 3795–810 | year = 2008 | month = October | pmid = 18843410 | doi = 10.1039/b808641a | url = | issn = }}</ref>

=== Full agonists ===

* [[EMD-386,088]] - potent and selective 5HT<sub>6</sub> agonist (EC<sub>50</sub> 1nM)<ref name="pmid16055331">{{cite journal | author = Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H | title = 2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT<sub>6</sub> receptor agonists | journal = Bioorg. Med. Chem. Lett. | volume = 15 | issue = 19 | pages = 4230–4 | year = 2005 | month = October | pmid = 16055331 | doi = 10.1016/j.bmcl.2005.06.067 | url =  }}</ref>
* [[2-Ethyl-5-methoxy-N,N-dimethyltryptamine]] (EMDT)<ref name="pmid10715164">{{cite journal | author = Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK | title = 2-Substituted tryptamines: agents with selectivity for 5-HT<sub>6</sub> serotonin receptors | journal = J. Med. Chem. | volume = 43 | issue = 5 | pages = 1011–8 | year = 2000 | pmid = 10715164 | doi = 10.1021/jm990550b }}</ref>
* [[WAY-181,187]]<ref name="pmid17625499">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.npp.1301503 | author = Schechter LE, Lin Q, Smith DL, ''et al.'' | title = Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 33 | issue = 6 | pages = 1323–35 | year = 2008 | month = May | pmid = 17625499 | doi = 10.1038/sj.npp.1301503}}</ref>
* [[WAY-208,466]]<ref name="pmid17625499">{{cite journal | unused_data = DUPLICATE DATA: doi = 10.1038/sj.npp.1301503 | author = Schechter LE, Lin Q, Smith DL, ''et al.'' | title = Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466 | journal = Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology | volume = 33 | issue = 6 | pages = 1323–35 | year = 2008 | month = May | pmid = 17625499 | doi = 10.1038/sj.npp.1301503}}</ref>
* N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (compound 11q)<ref name="pmid17948978">{{cite journal |author=Cole DC, Stock JR, Lennox WJ, Bernotas RC, Ellingboe JW, Boikess S, Coupet J, Smith DL, Leung L, Zhang GM, Feng X, Kelly MF, Galante R, Huang P, Dawson LA, Marquis K, Rosenzweig-Lipson S, Beyer CE, Schechter LE |title=Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist |journal=Journal of Medicinal Chemistry |volume=50 |issue=23 |pages=5535–8 |year=2007 |month=November |pmid=17948978 |doi=10.1021/jm070521y |url= |issn=}}</ref>
* ''N''-(inden-5-yl)imidazothiazole-5-sulfonamide (43): ''K''<sub>i</sub> = 4.5nM, EC<sub>50</sub> = 0.9nM, E<sub>max</sub> = 98%<ref name="pmid19159187">{{cite journal |author=Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R |title=Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists |journal=J. Med. Chem. |volume=52 |issue=3 |pages=675–87 |year=2009 |pmid=19159187 |doi=10.1021/jm8009469 |url=}}</ref>

=== Partial Agonists ===

* E-6801<ref name="pmid16865095">{{cite journal | author = Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ | title = Efficacy of selective 5-HT<sub>6</sub> receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways | journal = Br. J. Pharmacol. | volume = 148 | issue = 8 | pages = 1133–43 | year = 2006 | month = August | pmid = 16865095 | pmc = 1752021 | doi = 10.1038/sj.bjp.0706827 | url = | issn = }}</ref>
* E-6837<ref name="pmid16783408">{{cite journal | author = Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Mercé R, Holenz J, Vrang N, Sørensen RV, Heal D, Buschmann H, Pauwels PJ | title = Chronic 5-HT<sub>6</sub> receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats | journal = Br. J. Pharmacol. | volume = 148 | issue = 7 | pages = 973–83 | year = 2006 | month = August | pmid = 16783408 | pmc = 1751931 | doi = 10.1038/sj.bjp.0706807 | url = | issn = }}</ref>

=== Antagonists ===

* BVT-5182<ref name="pmid16537199">{{cite journal | author = Hugerth A, Brisander M, Wrange U, Kritikos M, Norrlind B, Svensson M, Bisrat M, Ostelius J | title = Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT<sub>6</sub> receptor antagonist | journal = Drug Dev Ind Pharm | volume = 32 | issue = 2 | pages = 185–96 | year = 2006 | month = February | pmid = 16537199 | doi = 10.1080/03639040500466122 | url = | issn = }}</ref>
* BVT-74316<ref name="pmid18068807">{{cite journal | author = Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H | title = Selective 5-HT<sub>6</sub> receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders | journal = Pharmacol. Ther. | volume = 117 | issue = 2 | pages = 207–31 | year = 2008 | month = February | pmid = 18068807 | doi = 10.1016/j.pharmthera.2007.08.006 | url = | issn = }}</ref>
* [[EGIS-12233]] - mixed 5-HT<sub>6</sub> / 5-HT<sub>7</sub> antagonist
* [[Latrepirdine]] (non-selective)<ref>Wu J, Li Q, Bezprozvanny I. Evaluation of Dimebon in cellular model of Huntington's disease. ''Molecular Neurodegeneration''. 2008 Oct 21;3-15. PMID 18939977</ref> and analogues<ref name="pmid19443217">{{cite journal |author=Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Okun IM, Tkachenko SE |title=Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists |journal=Bioorganic & Medicinal Chemistry Letters |volume=19 |issue=12 |pages=3183–7 |year=2009 |month=June |pmid=19443217 |doi=10.1016/j.bmcl.2009.04.128 |url=}}</ref>
* [[Lu AE58054]]
* [[MS-245]]
* [[PRX-07034]]
* [[SB-258,585]]
* [[SB-271,046]]
* [[SB-357,134]]
* [[SB-399,885]]
* [[SB-742,457]]
* [[Ro04-6790]]

== Genetics ==

The receptor is encoded by the ''HTR6'' gene. 
As the protein is a [[neuroreceptor]] it is possible that genetic variations in the gene would have an effect on brain, 
and research studies have investigated whether [[polymorphism (biology)|polymorphisms]] is associated with brain-related variables, such as [[neuropsychiatric disorder]]s.
For example, in 2004 one Chinese study reported an association between the [[C267T]] ([[rs1805054]]) polymorphism and [[Alzheimer's disease]].<ref name="pmid15531082">{{cite journal | author = Kan R, Wang B, Zhang C, Yang Z, Ji S, Lu Z, Zheng C, Jin F, Wang L | title = Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese | journal = Neurosci. Lett. | volume = 372 | issue = 1-2 | pages = 27–9 | year = 2004 | month = November | pmid = 15531082 | doi = 10.1016/j.neulet.2004.09.007 | url =  }}</ref>
Others have studied the polymorphism in relation to [[Parkinson's disease]].<ref name="pmid11889255">{{cite journal | author = Messina D, Annesi G, Serra P, Nicoletti G, Pasqua A, Annesi F, Tomaino C, Cirò-Candiano IC, Carrideo S, Caracciolo M, Spadafora P, Zappia M, Savettieri G, Quattrone A | title = Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease | journal = Neurology | volume = 58 | issue = 5 | pages = 828–9 | date=12 March 2002| pmid = 11889255 | url = http://www.neurology.org/cgi/content/citation/58/5/828 | issn = }}</ref>

== See also ==
* [[5-HT receptor]]

==References==
{{Reflist|2}}

== Further reading ==
{{Refbegin|2}}
{{PBB_Further_reading 
| citations = 
* {{cite journal  | author=Hoyer D, Hannon JP, Martin GR |title=Molecular, pharmacological and functional diversity of 5-HT receptors. |journal=Pharmacol. Biochem. Behav. |volume=71 |issue= 4 |pages= 533–54 |year= 2002 |pmid= 11888546 |doi=10.1016/S0091-3057(01)00746-8  }}
* {{cite journal  | author=Raymond JR, Mukhin YV, Gelasco A, ''et al.'' |title=Multiplicity of mechanisms of serotonin receptor signal transduction. |journal=Pharmacol. Ther. |volume=92 |issue= 2-3 |pages= 179–212 |year= 2002 |pmid= 11916537 |doi=10.1016/S0163-7258(01)00169-3  }}
* {{cite journal  | author=Van Oekelen D, Luyten WH, Leysen JE |title=5-HT2A and 5-HT2C receptors and their atypical regulation properties. |journal=Life Sci. |volume=72 |issue= 22 |pages= 2429–49 |year= 2003 |pmid= 12650852 |doi=10.1016/S0024-3205(03)00141-3  }}
* {{cite journal  | author=Dubertret C, Hanoun N, Adès J, ''et al.'' |title=Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia. |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=126 |issue= 1 |pages= 10–5 |year= 2004 |pmid= 15048641 |doi= 10.1002/ajmg.b.20120 }}
* {{cite journal  | author=Ullmer C, Schmuck K, Kalkman HO, Lübbert H |title=Expression of serotonin receptor mRNAs in blood vessels. |journal=FEBS Lett. |volume=370 |issue= 3 |pages= 215–21 |year= 1995 |pmid= 7656980 |doi=10.1016/0014-5793(95)00828-W  }}
* {{cite journal  | author=Kohen R, Metcalf MA, Khan N, ''et al.'' |title=Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. |journal=J. Neurochem. |volume=66 |issue= 1 |pages= 47–56 |year= 1996 |pmid= 8522988 |doi=10.1046/j.1471-4159.1996.66010047.x  }}
* {{cite journal  | author=Orlacchio A, Kawarai T, Paciotti E, ''et al.'' |title=Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease. |journal=Neurosci. Lett. |volume=325 |issue= 1 |pages= 13–6 |year= 2002 |pmid= 12023056 |doi=10.1016/S0304-3940(02)00221-5  }}
* {{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
* {{cite journal  | author=Ham BJ, Kim YH, Choi MJ, ''et al.'' |title=Serotonergic genes and personality traits in the Korean population. |journal=Neurosci. Lett. |volume=354 |issue= 1 |pages= 2–5 |year= 2004 |pmid= 14698468 |doi=10.1016/S0304-3940(03)00753-5  }}
* {{cite journal  | author=Bernotas R, Lenicek S, Antane S, ''et al.'' |title=1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands. |journal=Bioorg. Med. Chem. Lett. |volume=14 |issue= 22 |pages= 5499–502 |year= 2005 |pmid= 15482912 |doi= 10.1016/j.bmcl.2004.09.003 }}
* {{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 }}
* {{cite journal  | author=Kang H, Lee WK, Choi YH, ''et al.'' |title=Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the alpha subunit of GS protein. |journal=Biochem. Biophys. Res. Commun. |volume=329 |issue= 2 |pages= 684–92 |year= 2005 |pmid= 15737640 |doi= 10.1016/j.bbrc.2005.02.040 }}
* {{cite journal  | author=Tao WA, Wollscheid B, O'Brien R, ''et al.'' |title=Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry. |journal=Nat. Methods |volume=2 |issue= 8 |pages= 591–8 |year= 2005 |pmid= 16094384 |doi= 10.1038/nmeth776 }}
* {{cite journal  | author=Lorke DE, Lu G, Cho E, Yew DT |title=Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. |journal=BMC neuroscience |volume=7 |issue=  |pages= 36 |year= 2006 |pmid= 16640790 |doi= 10.1186/1471-2202-7-36  | pmc=1523198 }}
* {{cite journal  | author=Yun HM, Kim S, Kim HJ, ''et al.'' |title=The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. |journal=J. Biol. Chem. |volume=282 |issue= 8 |pages= 5496–505 |year= 2007 |pmid= 17189269 |doi= 10.1074/jbc.M606215200 }}
}}
{{Refend}}

== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2335 | title = 5-HT<sub>6</sub>  | accessdate = | author = | authorlink = | coauthors = | date = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | language = | archiveurl = | archivedate = | quote = }}
* {{MeshName|serotonin+6+receptor}}


{{NLM content}}
{{Cell signaling}}
{{G protein-coupled receptors}}
{{Serotonergics}}

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[[Category:G protein coupled receptors]]
[[Category:2Fix]]