Wikipedia

5-HT6receptor

The5HT6receptoris a subtype of5HT receptorthat binds theendogenousneurotransmitterserotonin(5-hydroxytryptamine, 5HT).[5]It is aG protein-coupled receptor(GPCR) that is coupled toGsand mediatesexcitatoryneurotransmission.[5]HTR6denotes thehumangeneencoding for thereceptor.[6]

HTR6
Identifiers
AliasesHTR6,5-HT6, 5-HT6R, 5-HT6 receptor, 5-hydroxytryptamine receptor 6
External IDsOMIM:601109;MGI:1196627;HomoloGene:673;GeneCards:HTR6;OMA:HTR6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3362

15565

Ensembl

ENSG00000158748

ENSMUSG00000028747

UniProt

P50406

Q9R1C8

RefSeq (mRNA)

NM_000871

NM_021358
NM_001377096

RefSeq (protein)

NP_000862

NP_067333
NP_001364025

Location (UCSC)Chr 1: 19.66 – 19.68 MbChr 4: 138.79 – 138.8 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Distribution

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The 5HT6receptor is expressed almost exclusively in thebrain.[7]It is distributed in various areas including, but not limited to, theolfactory tubercle,cerebral cortex(frontalandentorhinalregions),nucleus accumbens,striatum,caudate nucleus,hippocampus,and the molecular layer of thecerebellum.[5][8][9]Based on its abundance inextrapyramidal,limbic,andcorticalregions it can be suggested that the 5HT6receptor plays a role in functions likemotor control,emotionality,cognition,andmemory.[7][9][10]

Function

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Blockade of central 5HT6receptors has been shown to increaseglutamatergicandcholinergicneurotransmission in various brain areas,[11][12][13][14]whereas activation enhancesGABAergicsignaling in a widespread manner.[15]Antagonism of 5HT6receptors also facilitatesdopamineandnorepinephrinerelease in the frontal cortex,[14][16]while stimulation has the opposite effect.[15]

As a drug target for antagonists

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Despite the 5HT6receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[15]In parallel with this, 5HT6antagonists are hypothesized to improve cognition, learning, and memory.[17]Agents such aslatrepirdine,idalopirdine(Lu AE58054), andintepirdine(SB-742,457/RVT-101) were evaluated as novel treatments forAlzheimer's diseaseand other forms ofdementia.[14][18][19]However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6antagonists have also been shown to reduceappetiteand produceweight loss,and as a result,PRX-07034,BVT-5,182, and BVT-74,316 are being investigated for the treatment ofobesity.[20][21]

As a drug target for agonists

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Recently, the 5HT6agonistsWAY-181,187andWAY-208,466have been demonstrated to be active in rodent models ofdepression,anxiety,andobsessive-compulsive disorder(OCD), and such agents may be useful treatments for these conditions.[15][22]Additionally, indirect 5HT6activation may play a role in the therapeutic benefits ofserotonergicantidepressantslike theselective serotonin reuptake inhibitors(SSRIs) andtricyclic antidepressants(TCAs).[citation needed]

Ligands

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A large number of selective 5HT6ligands have now been developed.[23][24][25][26][27][28][29][30][31]

Agonists

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Full agonists

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Partial agonists

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  • E-6801[34]
  • E-6837– partial agonist at rat 5-HT6receptors. Orally active in rats, and caused weight loss with chronic administration[35]
  • EMD-386,088– potent partial agonist (EC50= 1 nM) but non-selective[36][37]
  • LSD– Emax= 60%[38]

Antagonists and inverse agonists

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Genetics

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Polymorphismsin the HTR6 gene are associated withneuropsychiatric disorders.For example, an association between theC267T(rs1805054) polymorphism andAlzheimer's diseasehas been shown.[45] Others have studied the polymorphism in relation toParkinson's disease.[46]

See also

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References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000158748–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000028747–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcKohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR,Roth BL,Hamblin MW (January 1996). "Cloning, characterization, and chromosomal localization of a human 5HT6serotonin receptor ".Journal of Neurochemistry.66(1): 47–56.doi:10.1046/j.1471-4159.1996.66010047.x.PMID8522988.S2CID35874409.
  6. ^"Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
  7. ^abWoolley ML, Marsden CA, Fone KC (February 2004). "5HT6receptors ".Current Drug Targets. CNS and Neurological Disorders.3(1): 59–79.doi:10.2174/1568007043482561.PMID14965245.
  8. ^Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs R, Schwartz JC (May 1993). "A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation ".Biochemical and Biophysical Research Communications.193(1): 268–76.doi:10.1006/bbrc.1993.1619.PMID8389146.
  9. ^abGérard C, Martres MP, Lefèvre K, Miquel MC, Vergé D, Lanfumey L, Doucet E, Hamon M, el Mestikawy S (January 1997). "Immuno-localization of serotonin 5-HT6receptor-like material in the rat central nervous system ".Brain Research.746(1–2): 207–19.doi:10.1016/S0006-8993(96)01224-3.PMID9037500.S2CID23364990.
  10. ^Hamon M, Doucet E, Lefèvre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Vergé D (August 1999)."Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5HT6receptors ".Neuropsychopharmacology.21(2 Suppl): 68S–76S.doi:10.1016/S0893-133X(99)00044-5.PMID10432491.
  11. ^Dawson LA, Nguyen HQ, Li P (May 2000)."In vivo effects of the 5HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5HT, glutamate and aspartate".British Journal of Pharmacology.130(1): 23–6.doi:10.1038/sj.bjp.0703288.PMC1572041.PMID10780993.
  12. ^Dawson LA, Nguyen HQ, Li P (November 2001)."The 5HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus".Neuropsychopharmacology.25(5): 662–8.doi:10.1016/S0893-133X(01)00265-2.PMID11682249.
  13. ^King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 2004). "5HT6receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism ".Neuropharmacology.47(2): 195–204.doi:10.1016/j.neuropharm.2004.03.012.PMID15223298.S2CID1736645.
  14. ^abcUpton N, Chuang TT, Hunter AJ, Virley DJ (July 2008)."5HT6receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease ".Neurotherapeutics.5(3): 458–69.doi:10.1016/j.nurt.2008.05.008.PMC5084247.PMID18625457.
  15. ^abcdSchechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (May 2008)."Neuropharmacological profile of novel and selective 5-HT6receptor agonists: WAY-181187 and WAY-208466 ".Neuropsychopharmacology.33(6): 1323–35.doi:10.1038/sj.npp.1301503.PMID17625499.
  16. ^Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). "5-HT6receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex ".Synapse.51(2): 158–64.doi:10.1002/syn.10288.PMID14618683.S2CID6539467.
  17. ^King MV, Marsden CA, Fone KC (September 2008). "A role for the 5HT(1A), 5HT4 and 5HT6receptors in learning and memory ".Trends in Pharmacological Sciences.29(9): 482–92.doi:10.1016/j.tips.2008.07.001.PMID19086256.
  18. ^Geldenhuys WJ, Van der Schyf CJ (2008)."Serotonin 5HT6receptor antagonists for the treatment of Alzheimer's disease ".Current Topics in Medicinal Chemistry.8(12): 1035–48.doi:10.2174/156802608785161420.PMID18691131.Archived from the original on 14 April 2013.{{cite journal}}:CS1 maint: unfit URL (link)
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  20. ^abHeal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 2008). "Selective 5-HT6receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders ".Pharmacology & Therapeutics.117(2): 207–31.doi:10.1016/j.pharmthera.2007.08.006.PMID18068807.
  21. ^Frassetto A, Zhang J, Lao JZ, White A, Metzger JM, Fong TM, Chen RZ (October 2008). "Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6receptor ".Brain Research.1236:140–4.doi:10.1016/j.brainres.2008.08.012.PMID18755168.S2CID33355136.
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  23. ^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 (October 2008). "Tricyclic azepine derivatives as selective brain penetrant 5-HT6receptor antagonists ".Bioorganic & Medicinal Chemistry Letters.18(20): 5698–700.doi:10.1016/j.bmcl.2008.08.010.PMID18793848.
  24. ^Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ (February 2009). "Identification of a series of benzoxazoles as potent 5-HT6ligands ".Bioorganic & Medicinal Chemistry Letters.19(4): 1115–7.doi:10.1016/j.bmcl.2008.12.107.PMID19152787.
  25. ^Lee M, Rangisetty JB, Pullagurla MR, Dukat M, Setola V, Roth BL, Glennon RA (March 2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6serotonin receptor ligands ".Bioorganic & Medicinal Chemistry Letters.15(6): 1707–11.doi:10.1016/j.bmcl.2005.01.031.PMID15745826.
  26. ^Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (August 2006). "Binding of sulfonyl-containing arylalkylamines at human 5HT6serotonin receptors ".Journal of Medicinal Chemistry.49(17): 5217–25.doi:10.1021/jm060469q.PMID16913710.
  27. ^Benhamú B, Martín-Fontecha M, Vázquez-Villa H, Pardo L, López-Rodríguez ML (2014)."Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease".J. Med. Chem.57(17): 7160–81.doi:10.1021/jm5003952.PMID24850589.
  28. ^van Loevezijn A, Venhorst J, Iwema Bakker WI, Lange JH, de Looff W, Henzen R, de Vries J, van de Woestijne RP, den Hartog AP, Verhoog S, van der Neut MA, de Bruin NM, Kruse CG (2016). "Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket".Bioorg. Med. Chem. Lett.26(6): 1605–11.doi:10.1016/j.bmcl.2016.02.001.PMID26876931.
  29. ^Ahmed M, Briggs MA, Bromidge SM, Buck T, Campbell L, Deeks NJ, Garner A, Gordon L, Hamprecht DW, Holland V, Johnson CN, Medhurst AD, Mitchell DJ, Moss SF, Powles J, Seal JT, Stean TO, Stemp G, Thompson M, Trail B, Upton N, Winborn K, Witty DR (November 2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6receptor antagonists ".Bioorganic & Medicinal Chemistry Letters.15(21): 4867–71.doi:10.1016/j.bmcl.2005.06.107.PMID16143522.
  30. ^Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). "Indene-based scaffolds. Design and synthesis of novel serotonin 5HT6receptor ligands ".Organic & Biomolecular Chemistry.6(20): 3795–810.doi:10.1039/b808641a.PMID18843410.
  31. ^Zhou P, Yan Y, Bernotas R, Harrison BL, Huryn D, Robichaud AJ, Zhang GM, Smith DL, Schechter LE (March 2005). "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6receptor ligands ".Bioorganic & Medicinal Chemistry Letters.15(5): 1393–6.doi:10.1016/j.bmcl.2005.01.005.PMID15713394.
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  34. ^Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (August 2006)."Efficacy of selective 5-HT6receptor ligands determined by monitoring 5-HT6receptor-mediated cAMP signaling pathways ".British Journal of Pharmacology.148(8): 1133–43.doi:10.1038/sj.bjp.0706827.PMC1752021.PMID16865095.
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Further reading

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