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5-HT2C receptor

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The correct title of this article is 5-HT2C receptor. It appears incorrectly here because of technical restrictions.
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5-hydroxytryptamine (serotonin) receptor 2C, also known as HTR2C, is a 5-HT2 receptor, but also denotes the human gene encoding it.[1]

FunctionEdit

LigandsEdit

Numerous (ex-)prescription, illicit and research drugs contain a 5-HT2C 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,[4] Ro60-0175,[5] mesulergine, metergoline, ritanserin, methiothepin, 5-methoxygramine, and many more.[6] Some compounds with a more pronounced selectivity for the 5-HT2C receptor subtype are listed below. Note, that in the following context the term "functional selectivity" does not refer to differentiation of transductional pathways.

Agonists Edit

  • A-372,159: partial agonist, Ki 3nM, 100x selectivity over 5-HT2B
  • MK-212
  • Ro60-0175
  • WAY-161,503
  • (5aR,9R)-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 profile[13]
  • (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: agonist, >300-fold functional selectivity over 5-HT2B and >70-fold over 5-HT2A[14]


Antagonists Edit

  • FR-260,010: high affinity, selective over 5-HT2A and many other receptors; orally active.[15]
  • RS-102,221: 100-fold selectivity compared to the 5-HT2A and -HT2B receptor subtypes[16]
  • SB-200,646: mixed 5-HT2B/2C antagonist
  • SB-206,553: mixed 5-HT2B/2C antagonist
  • SB-221,284: mixed 5-HT2B/2C antagonist
  • compound 15k: IC50 = 0.5 nM; >2000x selective over 5-HT1A, -2A, and -6, and dopamine D2–D4 receptors[18]


Inverse agonistsEdit

  • SB-228,357: mixed 5-HT2C inverse agonist / 5-HT2B antagonist


Mixed responseEdit

See alsoEdit

ReferencesEdit

  1. Stam NJ, Vanderheyden P, van Alebeek C, Klomp J, de Boer T, van Delft AM, Olijve W (November 1994). Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor. Eur. J. Pharmacol. 269 (3): 339–48.
  2. Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (July 2007). Serotonin 5-HT2C receptors regulate anxiety-like behavior. Genes Brain Behav. 6 (5): 491–6.
  3. Speake T, Kibble JD, Brown PD (March 2004). Kv1.1 and Kv1.3 channels contribute to the delayed-rectifying K+ conductance in rat choroid plexus epithelial cells. Am. J. Physiol., Cell Physiol. 286 (3): C611–20.
  4. Hackler EA, Turner GH, Gresch PJ, Sengupta S, Deutch AY, Avison MJ, Gore JC, Sanders-Bush E (2007). 5-Hydroxytryptamine2C receptor contribution to m-chlorophenylpiperazine and N-methyl-beta-carboline-3-carboxamide-induced anxiety-like behavior and limbic brain activation. J. Pharmacol. Exp. Ther. 320 (3): 1023–9.
  5. Higgins GA, Ouagazzal AM, Grottick AJ (2001). 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. Br. J. Pharmacol. 133 (4): 459–66.
  6. Lacivita E, Leopoldo M (2006). Selective agents for serotonin 2C (5-HT2C) receptor. Curr Top Med Chem 6 (18): 1927–70.
  7. 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 (2008). Lorcaserin, A Novel Selective Human 5-HT2C Agonist: In Vitro and In Vivo Pharmacological Characterization. J. Pharmacol. Exp. Ther..
  8. 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 (2005). Discovery and SAR of new benzazepines as potent and selective 5-HT2C receptor agonists for the treatment of obesity. Bioorg. Med. Chem. Lett. 15 (5): 1467–70.
  9. Lam DD, Przydzial MJ, Ridley SH, Yeo GS, Rochford JJ, O'Rahilly S, Heisler LK (2008). Serotonin 5-HT2C Receptor Agonist Promotes Hypophagia via Downstream Activation of Melanocortin 4 Receptors. Endocrinology 149 (3): 1323–8.
  10. Sabb AL, Vogel RL, Welmaker GS, Sabalski JE, Coupet J, Dunlop J, Rosenzweig-Lipson S, Harrison B. Cycloalkyl[b][1,4]benzodiazepinoindoles are agonists at the human 5-HT2C receptor. Bioorganic and Medicinal Chemistry Letters. 2004 May 17;14(10):2603-7. PMID 15109661
  11. Kimura Y, Hatanaka K, Naitou Y, Maeno K, Shimada I, Koakutsu A, Wanibuchi F, Yamaguchi T (2004). Pharmacological profile of YM348, a novel, potent and orally active 5-HT2C receptor agonist. Eur. J. Pharmacol. 483 (1): 37–43.
  12. Shimada I, Maeno K, Kazuta K, Kubota H, Kimizuka T, Kimura Y, Hatanaka K, Naitou Y, Wanibuchi F, Sakamoto S, Tsukamoto S (2008). Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine derivatives as 5-HT2C receptor agonists. Bioorg. Med. Chem. 16 (4): 1966–82.
  13. 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 (2006). Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT2C receptor agonists. Bioorg. Med. Chem. Lett. 16 (5): 1207–11.
  14. 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 (2007). 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-HT2C receptor. J. Med. Chem. 50 (6): 1365–79.
  15. Harada K, Aota M, Inoue T, Matsuda R, Mihara T, Yamaji T, Ishibashi K, Matsuoka N (2006). Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone. Eur. J. Pharmacol. 553 (1-3): 171–84.
  16. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM (1997). RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 36 (4-5): 621–9.
  17. 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
  18. Park CM, Kim SY, Park WK, Park NS, Seong CM (2008). Synthesis and structure-activity relationship of 1H-indole-3-carboxylic acid pyridine-3-ylamides: a novel series of 5-HT2C receptor antagonists. Bioorg. Med. Chem. Lett. 18 (14): 3844–7.
  19. 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 (2001). SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology 41 (2): 186–99.
  20. Berg KA, Navailles S, Sanchez TA, Silva YM, Wood MD, Spampinato U, Clarke WP (2006). 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. J. Pharmacol. Exp. Ther. 319 (1): 260-8.

External linksEdit

  • 5-HT2C. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

Further readingEdit


  • Niswender CM, Sanders-Bush E, Emeson RB (1999). Identification and characterization of RNA editing events within the 5-HT2C receptor.. Ann. N. Y. Acad. Sci. 861: 38–48.
  • Hoyer D, Hannon JP, Martin GR (2002). Molecular, pharmacological and functional diversity of 5-HT receptors.. Pharmacol. Biochem. Behav. 71 (4): 533–54.
  • Raymond JR, Mukhin YV, Gelasco A, et al. (2002). Multiplicity of mechanisms of serotonin receptor signal transduction.. Pharmacol. Ther. 92 (2-3): 179–212.
  • 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.
  • Reynolds GP, Templeman LA, Zhang ZJ (2005). The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment.. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (6): 1021–8.
  • Millan MJ (2006). Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies.. Therapie 60 (5): 441–60.
  • Milatovich A, Hsieh CL, Bonaminio G, et al. (1993). Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4).. Hum. Mol. Genet. 1 (9): 681–4.
  • Saltzman AG, Morse B, Whitman MM, et al. (1992). Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes.. Biochem. Biophys. Res. Commun. 181 (3): 1469–78.
  • Lappalainen J, Zhang L, Dean M, et al. (1995). Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C).. Genomics 27 (2): 274–9.
  • Tecott LH, Sun LM, Akana SF, et al. (1995). Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.. Nature 374 (6522): 542–6.
  • Stam NJ, Vanderheyden P, van Alebeek C, et al. (1995). Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor.. Eur. J. Pharmacol. 269 (3): 339–48.
  • Xie E, Zhu L, Zhao L, Chang LS (1996). The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variant.. Genomics 35 (3): 551–61.
  • Burns CM, Chu H, Rueter SM, et al. (1997). Regulation of serotonin-2C receptor G-protein coupling by RNA editing.. Nature 387 (6630): 303–8.
  • Brennan TJ, Seeley WW, Kilgard M, et al. (1997). Sound-induced seizures in serotonin 5-HT2c receptor mutant mice.. Nat. Genet. 16 (4): 387–90.
  • Ullmer C, Schmuck K, Figge A, Lübbert H (1998). Cloning and characterization of MUPP1, a novel PDZ domain protein.. FEBS Lett. 424 (1-2): 63–8.
  • Samochowiec J, Smolka M, Winterer G, et al. (1999). Association analysis between a Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene and neuronal hyperexcitability.. Am. J. Med. Genet. 88 (2): 126–30.
  • Cargill M, Altshuler D, Ireland J, et al. (1999). Characterization of single-nucleotide polymorphisms in coding regions of human genes.. Nat. Genet. 22 (3): 231–8.
  • Marshall SE, Bird TG, Hart K, Welsh KI (2000). Unified approach to the analysis of genetic variation in serotonergic pathways.. Am. J. Med. Genet. 88 (6): 621–7.
  • Backstrom JR, Price RD, Reasoner DT, Sanders-Bush E (2000). Deletion of the serotonin 5-HT2C receptor PDZ recognition motif prevents receptor phosphorylation and delays resensitization of receptor responses.. J. Biol. Chem. 275 (31): 23620–6.




This article incorporates text from the United States National Library of Medicine, which is in the public domain.Template:Transmembranereceptor-stub



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