5-HT2C receptor

5-hydroxytryptamine (serotonin) receptor 2C, also known as HTR2C, is a 5-HT₂ receptor, but also denotes the human gene encoding it.cite journal | author = Stam NJ, Vanderheyden P, van Alebeek C, Klomp J, de Boer T, van Delft AM, Olijve W | title = Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT_2C receptor | journal = Eur. J. Pharmacol. | volume = 269 | issue = 3 | pages = 339–48 | year = 1994 | month = November | pmid = 7895773 | doi = | url = | issn = ]

Function

* CNS: anxietycite journal | author = Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH | title = Serotonin 5-HT_2C receptors regulate anxiety-like behavior | journal = Genes Brain Behav. | volume = 6 | issue = 5 | pages = 491–6 | year = 2007 | month = July | pmid = 17451451 | doi = 10.1111/j.1601-183X.2007.00316.x | url = | issn = ]
* choroid plexus: cerebrospinal fluid (CSF) secretioncite journal | author = Speake T, Kibble JD, Brown PD | title = K_v1.1 and K_v1.3 channels contribute to the delayed-rectifying K⁺ conductance in rat choroid plexus epithelial cells | journal = Am. J. Physiol., Cell Physiol. | volume = 286 | issue = 3 | pages = C611–20 | year = 2004 | month = March | pmid = 14602579 | doi = 10.1152/ajpcell.00292.2003 | url = | issn = ]

Ligands

Numerous (ex-)prescription, illicit and research drugs contain a 5-HT_2C component in their binding profile, including fluoxetine, mianserin , clozapine, agomelatine, dextro-norfenfluramine , psilocin, DOI , α-methyl-serotonin, MK-212, ORG-37684, "m"-CPP , FG-7142,cite journal | author = Hackler EA, Turner GH, Gresch PJ, Sengupta S, Deutch AY, Avison MJ, Gore JC, Sanders-Bush E | title = 5-Hydroxytryptamine_2C receptor contribution to m-chlorophenylpiperazine and N-methyl-beta-carboline-3-carboxamide-induced anxiety-like behavior and limbic brain activation | journal = J. Pharmacol. Exp. Ther. | volume = 320 | issue = 3 | pages = 1023–9 | year = 2007 | pmid = 17138863 | doi = 10.1124/jpet.106.113357 | issn = ] Ro60-0175 ,cite journal | author = Higgins GA, Ouagazzal AM, Grottick AJ | title = Influence of the 5-HT(2C) receptor antagonist SB242,084 on behaviour produced by the 5-HT₂ agonist Ro60-0175 and the indirect 5-HT agonist dexfenfluramine | journal = Br. J. Pharmacol. | volume = 133 | issue = 4 | pages = 459–66 | year = 2001 | pmid = 11399662 | doi = 10.1038/sj.bjp.0704082 | issn = ] mesulergine, metergoline, ritanserin, methiothepin, 5-methoxygramine , and many more.cite journal | author = Lacivita E, Leopoldo M | title = Selective agents for serotonin 2C (5-HT_2C) receptor | journal = Curr Top Med Chem | volume = 6 | issue = 18 | pages = 1927–70 | year = 2006 | pmid = 17017967 | doi = 10.2174/156802606778522168 | issn = ] Some compounds with a more pronounced selectivity for the 5-HT_2C receptor subtype are listed below. Note, that in the following context the term "functional selectivity" does not refer to differentiation of transductional pathways.

Agonists

*YM-348: potent, full agonist, high affinity, high functional selectivity, orally activecite journal | author = Kimura Y, Hatanaka K, Naitou Y, Maeno K, Shimada I, Koakutsu A, Wanibuchi F, Yamaguchi T | title = Pharmacological profile of YM348, a novel, potent and orally active 5-HT_2C receptor agonist | journal = Eur. J. Pharmacol. | volume = 483 | issue = 1 | pages = 37–43 | year = 2004 | pmid = 14709324 | doi = 10.1016/j.ejphar.2003.10.004 | issn = ] cite journal | author = Shimada I, Maeno K, Kazuta K, Kubota H, Kimizuka T, Kimura Y, Hatanaka K, Naitou Y, Wanibuchi F, Sakamoto S, Tsukamoto S | title = Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo [2,3-g] indazol-1-yl)ethylamine derivatives as 5-HT_2C receptor agonists | journal = Bioorg. Med. Chem. | volume = 16 | issue = 4 | pages = 1966–82 | year = 2008 | pmid = 18035544 | doi = 10.1016/j.bmc.2007.10.100 | issn = ]

*(5a"R",9"R")-2- [(cyclopropylmethoxy)methyl] -5,5a,6,7,8,9-hexahydro-9-methyl-pyrido [3′,2′:4,5] pyrrolo [1,2-a] pyrazine: potent, full agonist with an outstanding selectivity profilecite journal | author = Richter HG, Adams DR, Benardeau A, Bickerdike MJ, Bentley JM, Blench TJ, Cliffe IA, Dourish C, Hebeisen P, Kennett GA, Knight AR, Malcolm CS, Mattei P, Misra A, Mizrahi J, Monck NJ, Plancher JM, Roever S, Roffey JR, Taylor S, Vickers SP | title = Synthesis and biological evaluation of novel hexahydro-pyrido [3',2':4,5] pyrrolo [1,2-a] pyrazines as potent and selective 5-HT_2C receptor agonists | journal = Bioorg. Med. Chem. Lett. | volume = 16 | issue = 5 | pages = 1207–11 | year = 2006 | pmid = 16361098 | doi = 10.1016/j.bmcl.2005.11.083 | issn = ]

*("R")-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino [2,1-a] isoindol-6(2"H")-one: agonist, >300-fold functional selectivity over 5-HT_2B and >70-fold over 5-HT_2Acite journal | author = Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA | title = Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino [2,1-a] isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT_2C receptor | journal = J. Med. Chem. | volume = 50 | issue = 6 | pages = 1365–79 | year = 2007 | pmid = 17315987 | doi = 10.1021/jm0612968 | issn = ]

*Lorcaserin: full agonist, fair selectivity profilecite journal | author = Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shama H, Smith B, Chalmers D, Behan D | title = Lorcaserin, A Novel Selective Human 5-HT_2C Agonist: In Vitro and In Vivo Pharmacological Characterization | journal = J. Pharmacol. Exp. Ther. | volume = | issue = | pages = | year = 2008 | pmid = 18252809 | doi = 10.1124/jpet.107.133348 | issn = ] cite journal | author = Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Thomsen WJ, Saldana HR, Whelan KT, Menzaghi F, Webb RR, Beeley NR | title = Discovery and SAR of new benzazepines as potent and selective 5-HT_2C receptor agonists for the treatment of obesity | journal = Bioorg. Med. Chem. Lett. | volume = 15 | issue = 5 | pages = 1467–70 | year = 2005 | pmid = 15713408 | doi = 10.1016/j.bmcl.2004.12.080 | issn = ] cite journal | author = Lam DD, Przydzial MJ, Ridley SH, Yeo GS, Rochford JJ, O'Rahilly S, Heisler LK | title = Serotonin 5-HT2C Receptor Agonist Promotes Hypophagia via Downstream Activation of Melanocortin 4 Receptors | journal = Endocrinology | volume = 149 | issue = 3 | pages = 1323–8 | year = 2008 | pmid = 18039773 | doi = 10.1210/en.2007-1321 | issn = ]

Antagonists

*compound 15k: IC50 = 0.5 nM; >2000x selective over 5-HT1A, -2A, and -6, and dopamine D2–D4 receptorscite journal |author=Park CM, Kim SY, Park WK, Park NS, Seong CM |title=Synthesis and structure-activity relationship of 1H-indole-3-carboxylic acid pyridine-3-ylamides: a novel series of 5-HT2C receptor antagonists |journal=Bioorg. Med. Chem. Lett. |volume=18 |issue=14 |pages=3844–7 |year=2008 |pmid=18602261 |doi=10.1016/j.bmcl.2008.06.064 |url=]

*FR-260,010: high affinity, selective over 5-HT_2A and many other receptors; orally active.cite journal | author = Harada K, Aota M, Inoue T, Matsuda R, Mihara T, Yamaji T, Ishibashi K, Matsuoka N | title = Anxiolytic activity of a novel potent serotonin 5-HT_2C receptor antagonist FR260010: a comparison with diazepam and buspirone | journal = Eur. J. Pharmacol. | volume = 553 | issue = 1-3 | pages = 171–84 | year = 2006 | pmid = 17074317 | doi = 10.1016/j.ejphar.2006.09.042 | issn = ]

*RS-102,221: 100-fold selectivity compared to the 5-HT_2A and -HT_2B receptor subtypescite journal | author = Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM | title = RS-102221: a novel high affinity and selective, 5-HT_2C receptor antagonist | journal = Neuropharmacology | volume = 36 | issue = 4-5 | pages = 621–9 | year = 1997 | pmid = 9225287 | doi = 10.1016/S0028-3908(97)00049-X | issn = ]

*SB-242,084 [Bromidge SM, Duckworth M, Forbes IT, Ham P, King FD, Thewlis KM, Blaney FE, Naylor CB, Blackburn TP, Kennett GA, Wood MD, Clarke SE. 6-Chloro-5-methyl-1- [2- [(2-methyl-3-pyridyl)oxy] -5-pyridyl] carbamoyl] - indoline (SB-242084): the first selective and brain penetrant 5-HT2C receptor antagonist. "Journal of Medicinal Chemistry". 1997 Oct 24;40(22):3494-6. PMID 9357513]

Mixed response

A more extensive examination on signal transduction was carried out for
*SB-243,213: high affinity, >100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels; long duration of action in vivo (>8 h); anxiolytic-like effects.cite journal | author = Wood MD, Reavill C, Trail B, Wilson A, Stean T, Kennett GA, Lightowler S, Blackburn TP, Thomas D, Gager TL, Riley G, Holland V, Bromidge SM, Forbes IT, Middlemiss DN | title = SB-243213; a selective 5-HT_2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety | journal = Neuropharmacology | volume = 41 | issue = 2 | pages = 186–99 | year = 2001 | pmid = 11489455 | doi = 10.1016/S0028-3908(01)00054-5 | issn = ] "Inverse agonist" for the PLA2 response, for GTPgammaS binding, for reduction of constitutive desensitization, and for enhancement of dopamine release in the rat nucleus accumbens. "Silent antagonist" for the PLC cascade.cite journal | author = Berg KA, Navailles S, Sanchez TA, Silva YM, Wood MD, Spampinato U, Clarke WP | title = Differential effects of 5-methyl-1-{ [2- [(2-methyl-3-pyridyl)oxyl] -5-pyridyl] carbamoyl}-6-trifluoromethylindone (SB 243213) on 5-hydroxytryptamine (2C) receptor-mediated responses | journal = J. Pharmacol. Exp. Ther. | volume = 319 | issue = 1 | pages = 260-8 | year = 2006 | pmid = 16807362 | doi = 10.1124/jpet.106.104448 | issn = ] (See also functional selectivity).

ee also

* 5-HT receptor

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Niswender CM, Sanders-Bush E, Emeson RB |title=Identification and characterization of RNA editing events within the 5-HT2C receptor. |journal=Ann. N. Y. Acad. Sci. |volume=861 |issue= |pages= 38–48 |year= 1999 |pmid= 9928237 |doi=
*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=
*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=
*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=
*cite journal | author=Reynolds GP, Templeman LA, Zhang ZJ |title=The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=29 |issue= 6 |pages= 1021–8 |year= 2005 |pmid= 15953671 |doi= 10.1016/j.pnpbp.2005.03.019
*cite journal | author=Millan MJ |title=Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. |journal=Therapie |volume=60 |issue= 5 |pages= 441–60 |year= 2006 |pmid= 16433010 |doi=
*cite journal | author=Milatovich A, Hsieh CL, Bonaminio G, "et al." |title=Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). |journal=Hum. Mol. Genet. |volume=1 |issue= 9 |pages= 681–4 |year= 1993 |pmid= 1302605 |doi=
*cite journal | author=Saltzman AG, Morse B, Whitman MM, "et al." |title=Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes. |journal=Biochem. Biophys. Res. Commun. |volume=181 |issue= 3 |pages= 1469–78 |year= 1992 |pmid= 1722404 |doi=
*cite journal | author=Lappalainen J, Zhang L, Dean M, "et al." |title=Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). |journal=Genomics |volume=27 |issue= 2 |pages= 274–9 |year= 1995 |pmid= 7557992 |doi= 10.1006/geno.1995.1042
*cite journal | author=Tecott LH, Sun LM, Akana SF, "et al." |title=Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. |journal=Nature |volume=374 |issue= 6522 |pages= 542–6 |year= 1995 |pmid= 7700379 |doi= 10.1038/374542a0
*cite journal | author=Stam NJ, Vanderheyden P, van Alebeek C, "et al." |title=Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor. |journal=Eur. J. Pharmacol. |volume=269 |issue= 3 |pages= 339–48 |year= 1995 |pmid= 7895773 |doi=
*cite journal | author=Xie E, Zhu L, Zhao L, Chang LS |title=The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variant. |journal=Genomics |volume=35 |issue= 3 |pages= 551–61 |year= 1996 |pmid= 8812491 |doi= 10.1006/geno.1996.0397
*cite journal | author=Burns CM, Chu H, Rueter SM, "et al." |title=Regulation of serotonin-2C receptor G-protein coupling by RNA editing. |journal=Nature |volume=387 |issue= 6630 |pages= 303–8 |year= 1997 |pmid= 9153397 |doi= 10.1038/387303a0
*cite journal | author=Brennan TJ, Seeley WW, Kilgard M, "et al." |title=Sound-induced seizures in serotonin 5-HT2c receptor mutant mice. |journal=Nat. Genet. |volume=16 |issue= 4 |pages= 387–90 |year= 1997 |pmid= 9241279 |doi= 10.1038/ng0897-387
*cite journal | author=Ullmer C, Schmuck K, Figge A, Lübbert H |title=Cloning and characterization of MUPP1, a novel PDZ domain protein. |journal=FEBS Lett. |volume=424 |issue= 1-2 |pages= 63–8 |year= 1998 |pmid= 9537516 |doi=
*cite journal | author=Samochowiec J, Smolka M, Winterer G, "et al." |title=Association analysis between a Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene and neuronal hyperexcitability. |journal=Am. J. Med. Genet. |volume=88 |issue= 2 |pages= 126–30 |year= 1999 |pmid= 10206230 |doi=
*cite journal | author=Cargill M, Altshuler D, Ireland J, "et al." |title=Characterization of single-nucleotide polymorphisms in coding regions of human genes. |journal=Nat. Genet. |volume=22 |issue= 3 |pages= 231–8 |year= 1999 |pmid= 10391209 |doi= 10.1038/10290
*cite journal | author=Marshall SE, Bird TG, Hart K, Welsh KI |title=Unified approach to the analysis of genetic variation in serotonergic pathways. |journal=Am. J. Med. Genet. |volume=88 |issue= 6 |pages= 621–7 |year= 2000 |pmid= 10581480 |doi=
*cite journal | author=Backstrom JR, Price RD, Reasoner DT, Sanders-Bush E |title=Deletion of the serotonin 5-HT_2C receptor PDZ recognition motif prevents receptor phosphorylation and delays resensitization of receptor responses. |journal=J. Biol. Chem. |volume=275 |issue= 31 |pages= 23620–6 |year= 2000 |pmid= 10816555 |doi= 10.1074/jbc.M000922200

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