5-HT6 receptor
(Preusmjereno sa stranice 5-HT6)
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5-HT6 receptor je tip 5-HT receptora za koji se vezuje endogeni neurotransmiter serotonin (5-hidroksitriptamin, 5-HT).[1] On je G protein-spregnuti receptor koji deluje kroz Gs/Go i posreduje ekscitatornu neurotransmisiju.[1] HTR6 je i oznaka za humani gen koji kodira ovaj receptor.[2]
| 5-hidroksitriptaminski (serotoninski) receptor 6 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Identifikatori | |||||||||||
| Simboli | HTR6; 5-HT6; 5-HT6R | ||||||||||
| Vanjski ID | OMIM: 601109 MGI: 1196627 HomoloGene: 673 IUPHAR: 5-HT6 GeneCards: HTR6 Gene | ||||||||||
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| Pregled RNK izražavanja | |||||||||||
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| podaci | |||||||||||
| Ortolozi | |||||||||||
| Vrsta | Čovek | Miš | |||||||||
| Entrez | 3362 | 15565 | |||||||||
| Ensembl | ENSG00000158748 | ENSMUSG00000028747 | |||||||||
| UniProt | P50406 | Q14AW8 | |||||||||
| RefSeq (mRNA) | NM_000871 | NM_021358 | |||||||||
| RefSeq (protein) | NP_000862 | NP_067333 | |||||||||
| Lokacija (UCSC) | Chr 1: 19.86 - 19.88 Mb | Chr 4: 138.33 - 138.35 Mb | |||||||||
| PubMed pretraga | [1] | [2] | |||||||||
Distribucija uredi
5-HT6 receptor je skoro isključivo izražen u mozgu.[3] On je distribuiran u više oblasti, među kojima su mirisne tuberkule, cerebralni korteks (frontalni i entorinalni regioni), nucleus accumbens, striatum, caudate nucleus, hipokampus, i mali mozak.[4][5][6] Usled njegove zastupljenosti u ekstrapiramidalnim, limbičnim, i korteksnim regionima smatra se da 5-HT6 receptor učestvuje u motornoj kontroli, emocionalnosti, kogniciji, i memoriji.[3][6][7]
Funkcija uredi
Za blokadu centralnih 5-HT6 receptora je pokazano da povišava glutamatergičku i holinergičku neurotransmisiju u više oblasti mozga,[8][9][10][11] dok aktivacija uvećava opštu GABA signalizaciju.[12] Antagonizam 5-HT6 receptora takođe omogućava otpuštanje dopamina i norepinefrina frontalnom korteksu,[11][13] dok stimulacija ima suprotni efekat.[12]
Ligandi uredi
Velik broj selektivnih 5-HT6 liganda je razvijen.[14][15][16][17][18][19][20]
Puni agonisti uredi
- EMD-386,088 - potentan i selektivan 5HT6 agonist (EC50 1nM)[21]
- 2-Etil-5-metoksi-N,N-dimetiltriptamin (EMDT)[22]
- WAY-181,187[12]
- WAY-208,466[12]
- N1-(6-hloroimidazo[2,1-b][1,3]tiazol-5-sulfonil)triptamin (jedinjenje 11q)[23]
- N-(inden-5-il)imidazotiazol-5-sulfonamid (43): Ki = 4.5nM, EC50 = 0.9nM, Emax = 98%[24]
- E-6837 - Pun agonist na ljudskim 5-HT6 receptorima
Parcijalni agonisti uredi
Antagonisti uredi
- BVT-5182[27]
- BVT-74316[28]
- EGIS-12233 - mešoviti 5-HT6 / 5-HT7 antagonist
- Latrepirdin (nije selektivan)[29] i analozi[30]
- Lu AE58054
- MS-245
- PRX-07034
- SB-258,585
- SB-271,046
- SB-357,134
- SB-399,885
- SB-742,457
- Ro04-6790
- Atipični antipsihotici (olanzapin, asenapin, klozapin)
- WAY-255315 / SAM-315: Ki = 1.1nM, IC = 13 nM[31]
Vidi još uredi
Reference uredi
- ↑ 1,0 1,1 Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). „Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor”. J. Neurochem. 66 (1): 47–56. DOI:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
- ↑ „Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6”.
- ↑ 3,0 3,1 Woolley ML, Marsden CA, Fone KC (February 2004). „5-ht6 receptors”. Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. DOI:10.2174/1568007043482561. PMID 14965245.
- ↑ Kohen R, Metcalf MA, Khan N, et al. (January 1996). „Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor”. Journal of Neurochemistry 66 (1): 47–56. DOI:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.[mrtav link]
- ↑ Ruat M, Traiffort E, Arrang JM, et al. (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. PMID 8389146.
- ↑ 6,0 6,1 Gérard C, Martres MP, Lefèvre K, et al. (January 1997). „Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system”. Brain Research 746 (1-2): 207–19. DOI:10.1016/S0006-8993(96)01224-3. PMID 9037500.
- ↑ Hamon M, Doucet E, Lefèvre K, et al. (August 1999). „Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors”. Neuropsychopharmacology 21 (2 Suppl): 68S–76S. DOI:10.1016/S0893-133X(99)00044-5. PMID 10432491.
- ↑ Dawson LA, Nguyen HQ, Li P (May 2000). „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”. British Journal of Pharmacology 130 (1): 23–6. DOI:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993.
- ↑ Dawson LA, Nguyen HQ, Li P (November 2001). „The 5-HT(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. PMID 11682249.
- ↑ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 2004). „5-HT6 receptor 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. PMID 15223298.
- ↑ 11,0 11,1 Upton N, Chuang TT, Hunter AJ, Virley DJ (July 2008). „5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease”. Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 5 (3): 458–69. DOI:10.1016/j.nurt.2008.05.008. PMID 18625457.
- ↑ 12,0 12,1 12,2 12,3 Schechter LE, Lin Q, Smith DL, et al. (May 2008). „Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466”. Neuropsychopharmacology 33 (6): 1323–35. DOI:10.1038/sj.npp.1301503. PMID 17625499.
- ↑ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). „5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex”. Synapse 51 (2): 158–64. DOI:10.1002/syn.10288. PMID 14618683.
- ↑ 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-HT6 receptor antagonists”. Bioorg. Med. Chem. Lett. 18 (20): 5698–700. DOI:10.1016/j.bmcl.2008.08.010. PMID 18793848.
- ↑ 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-HT6 ligands”. Bioorg. Med. Chem. Lett. 19 (4): 1115–7. DOI:10.1016/j.bmcl.2008.12.107. PMID 19152787.
- ↑ Lee M, Rangisetty JB, Pullagurla MR, et al (2005). „1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands”. Bioorg. Med. Chem. Lett. 15 (6): 1707–11. DOI:10.1016/j.bmcl.2005.01.031. PMID 15745826.
- ↑ Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (2006). „Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors”. J. Med. Chem. 49 (17): 5217–25. DOI:10.1021/jm060469q. PMID 16913710.
- ↑ Zhou P, Yan Y, Bernotas R, et al (2005). „4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands”. Bioorg. Med. Chem. Lett. 15 (5): 1393–6. DOI:10.1016/j.bmcl.2005.01.005. PMID 15713394.
- ↑ Ahmed M, Briggs MA, Bromidge SM, et al (2005). „Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists”. Bioorg. Med. Chem. Lett. 15 (21): 4867–71. DOI:10.1016/j.bmcl.2005.06.107. PMID 16143522.
- ↑ Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). „Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6 receptor ligands”. Org. Biomol. Chem. 6 (20): 3795–810. DOI:10.1039/b808641a. PMID 18843410.
- ↑ Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H (October 2005). „2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists”. Bioorg. Med. Chem. Lett. 15 (19): 4230–4. DOI:10.1016/j.bmcl.2005.06.067. PMID 16055331.
- ↑ Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (2000). „2-Substituted tryptamines: agents with selectivity for 5-HT6 serotonin receptors”. J. Med. Chem. 43 (5): 1011–8. DOI:10.1021/jm990550b. PMID 10715164.
- ↑ 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 (November 2007). „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 of Medicinal Chemistry 50 (23): 5535–8. DOI:10.1021/jm070521y. PMID 17948978.
- ↑ Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (2009). „Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists”. J. Med. Chem. 52 (3): 675–87. DOI:10.1021/jm8009469. PMID 19159187.
- ↑ Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (August 2006). „Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways”. Br. J. Pharmacol. 148 (8): 1133–43. DOI:10.1038/sj.bjp.0706827. PMC 1752021. PMID 16865095.
- ↑ Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Mercé R, Holenz J, Vrang N, Sørensen RV, Heal D, Buschmann H, Pauwels PJ (August 2006). „Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats”. Br. J. Pharmacol. 148 (7): 973–83. DOI:10.1038/sj.bjp.0706807. PMC 1751931. PMID 16783408.
- ↑ Hugerth A, Brisander M, Wrange U, Kritikos M, Norrlind B, Svensson M, Bisrat M, Ostelius J (February 2006). „Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT6 receptor antagonist”. Drug Dev Ind Pharm 32 (2): 185–96. DOI:10.1080/03639040500466122. PMID 16537199.
- ↑ Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 2008). „Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders”. Pharmacol. Ther. 117 (2): 207–31. DOI:10.1016/j.pharmthera.2007.08.006. PMID 18068807.
- ↑ Wu, J; Li, Q; Bezprozvanny, I (2008). „Evaluation of Dimebon in cellular model of Huntington's disease.”. Molecular neurodegeneration 3: 15. DOI:10.1186/1750-1326-3-15. PMC 2577671. PMID 18939977.
- ↑ Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Okun IM, Tkachenko SE (June 2009). „Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists”. Bioorganic & Medicinal Chemistry Letters 19 (12): 3183–7. DOI:10.1016/j.bmcl.2009.04.128. PMID 19443217.
- ↑ Liu KG, Robichaud AJ, Bernotas RC, Yan Y, Lo JR, Zhang MY, Hughes ZA, Huselton C, Zhang GM, Zhang JY, Kowal DM, Smith DL, Schechter LE, Comery TA (2010). „5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists”. J Med Chem. 53 (21): 7639-46. PMID 20932009.
Literatura uredi
- Hoyer D, Hannon JP, Martin GR (2002). „Molecular, pharmacological and functional diversity of 5-HT receptors.”. Pharmacol. Biochem. Behav. 71 (4): 533–54. DOI:10.1016/S0091-3057(01)00746-8. PMID 11888546.
- Raymond JR, Mukhin YV, Gelasco A, et al. (2002). „Multiplicity of mechanisms of serotonin receptor signal transduction.”. Pharmacol. Ther. 92 (2-3): 179–212. DOI:10.1016/S0163-7258(01)00169-3. PMID 11916537.
- Van Oekelen D, Luyten WH, Leysen JE (2003). „5-HT2A and 5-HT2C receptors and their atypical regulation properties.”. Life Sci. 72 (22): 2429–49. DOI:10.1016/S0024-3205(03)00141-3. PMID 12650852.
- Dubertret C, Hanoun N, Adès J, et al. (2004). „Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia.”. Am. J. Med. Genet. B Neuropsychiatr. Genet. 126 (1): 10–5. DOI:10.1002/ajmg.b.20120. PMID 15048641.
- Ullmer C, Schmuck K, Kalkman HO, Lübbert H (1995). „Expression of serotonin receptor mRNAs in blood vessels.”. FEBS Lett. 370 (3): 215–21. DOI:10.1016/0014-5793(95)00828-W. PMID 7656980.
- Kohen R, Metcalf MA, Khan N, et al. (1996). „Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor.”. J. Neurochem. 66 (1): 47–56. DOI:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
- Orlacchio A, Kawarai T, Paciotti E, et al. (2002). „Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease.”. Neurosci. Lett. 325 (1): 13–6. DOI:10.1016/S0304-3940(02)00221-5. PMID 12023056.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). „Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. DOI:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ham BJ, Kim YH, Choi MJ, et al. (2004). „Serotonergic genes and personality traits in the Korean population.”. Neurosci. Lett. 354 (1): 2–5. DOI:10.1016/S0304-3940(03)00753-5. PMID 14698468.
- Bernotas R, Lenicek S, Antane S, et al. (2005). „1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands.”. Bioorg. Med. Chem. Lett. 14 (22): 5499–502. DOI:10.1016/j.bmcl.2004.09.003. PMID 15482912.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). „The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”. Genome Res. 14 (10B): 2121–7. DOI:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Kang H, Lee WK, Choi YH, et al. (2005). „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.”. Biochem. Biophys. Res. Commun. 329 (2): 684–92. DOI:10.1016/j.bbrc.2005.02.040. PMID 15737640.
- Tao WA, Wollscheid B, O'Brien R, et al. (2005). „Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry.”. Nat. Methods 2 (8): 591–8. DOI:10.1038/nmeth776. PMID 16094384.
- Lorke DE, Lu G, Cho E, Yew DT (2006). „Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients.”. BMC neuroscience 7: 36. DOI:10.1186/1471-2202-7-36. PMC 1523198. PMID 16640790.
- Yun HM, Kim S, Kim HJ, et al. (2007). „The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn.”. J. Biol. Chem. 282 (8): 5496–505. DOI:10.1074/jbc.M606215200. PMID 17189269.
Spoljašnje veze uredi
- „5-HT6”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2015-04-02.
- MeSH serotonin+6+receptor