5-hydroxytryptamine 2C receptor

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==Description==
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==Source Organism==
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'''5-hydroxytryptamine (serotonin) receptor 2C''', also known as '''HTR2C''', is a [[5-HT2 receptor|5-HT<sub>2</sub> receptor]], but also denotes the human [[gene]] encoding it.<ref name="pmid7895773">{{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<sub>2C</sub> receptor | journal = Eur. J. Pharmacol. | volume = 269 | issue = 3 | pages = 339–48 | year = 1994 | month = November | pmid = 7895773 | doi = | url = | issn = }}</ref>
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==General Characterstics==
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===Source Organism===
Canis familiaris (Dog).
Canis familiaris (Dog).
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==Taxomomy==
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===Taxomomy===
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae;Canis.
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae;Canis.
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==Subcellular Localization==
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===Subcellular Localization===
Cell membrane; multi-pass membrane protein (By similarity).
Cell membrane; multi-pass membrane protein (By similarity).
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==Developmental Stage==
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===Similarity===
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==Similarity==
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Belongs to the G-protein coupled receptor 1 family.  
Belongs to the G-protein coupled receptor 1 family.  
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==Post translational Modification==
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===Post translational Modification===
N-glycosylated (By similarity).
N-glycosylated (By similarity).
==Function==
==Function==
This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system (By similarity).
This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system (By similarity).
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==Ligands==
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Numerous (ex-)prescription, illicit and research drugs contain a 5-HT<sub>2C</sub> component in their binding profile, including [[fluoxetine]], [[mianserin]]<!--inverse agonist-->, [[clozapine]], [[agomelatine]], dextro-[[norfenfluramine]]<!--full agonist-->, [[psilocin]], [[2,5-Dimethoxy-4-iodoamphetamine|DOI]]<!--partial agonist-->, α-methyl-serotonin, MK-212, ORG-37684, [[1-(3-Chlorophenyl)piperazine|''m''-CPP]]<!--partial agonist-->, FG-7142,<ref name="pmid17138863">{{cite journal | author = Hackler EA, Turner GH, Gresch PJ, Sengupta S, Deutch AY, Avison MJ, Gore JC, Sanders-Bush E | title = 5-Hydroxytryptamine<sub>2C</sub> 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 = }}</ref> Ro60-0175<!--agonist-->,<ref name="pmid11399662">{{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-HT<sub>2</sub> 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 = }}</ref> [[mesulergine]], [[metergoline]], [[ritanserin]], [[methiothepin]], 5-methoxy[[gramine]]<!--silent antagonist-->, and many more.<ref name="pmid17017967">{{cite journal | author = Lacivita E, Leopoldo M | title = Selective agents for serotonin 2C (5-HT<sub>2C</sub>) receptor | journal = Curr Top Med Chem | volume = 6 | issue = 18 | pages = 1927–70 | year = 2006 | pmid = 17017967 | doi = 10.2174/156802606778522168 | issn = }}</ref> Some compounds with a more pronounced selectivity for the 5-HT<sub>2C</sub> receptor subtype are listed below. Note, that in the following context the term "functional selectivity" does not refer to differentiation of transductional pathways.
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=== Agonists ===
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* 1-Methylpsilocin
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* [[A-372,159]]: partial agonist, Ki 3nM, 100x selectivity over 5-HT<sub>2B</sub>
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* CP-809,101
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* [[Lorcaserin]]: full agonist, fair selectivity profile<ref name="pmid18252809">{{cite 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<sub>2C</sub> 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 = }}</ref><ref name="pmid15713408">{{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<sub>2C</sub> 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 = }}</ref><ref name="pmid18039773">{{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 = }}</ref>
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* MK-212
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* Ro60-0175
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* [[Vabicaserin]]
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* WAY-629<ref>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</ref>
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* WAY-161,503
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* [[YM-348]]: potent, [[full agonist]], high [[Dissociation constant#Protein-Ligand binding|affinity]], high functional selectivity, orally active<ref name="pmid14709324">{{cite 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<sub>2C</sub> 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 = }}</ref><ref name="pmid18035544">{{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<sub>2C</sub> 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 = }}</ref>
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* (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 profile<ref name="pmid16361098">{{cite 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<sub>2C</sub> 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 = }}</ref>
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* (''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<sub>2B</sub> and >70-fold over 5-HT<sub>2A</sub><ref name="pmid17315987">{{cite 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<sub>2C</sub> receptor | journal = J. Med. Chem. | volume = 50 | issue = 6 | pages = 1365–79 | year = 2007 | pmid = 17315987 | doi = 10.1021/jm0612968 | issn = }}</ref>
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=== Antagonists ===
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* FR-260,010: high affinity, selective over 5-HT<sub>2A</sub> and many other receptors; orally active.<ref name="pmid17074317">{{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<sub>2C</sub> 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 = }}</ref>
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* [[RS-102,221]]: 100-fold selectivity compared to the 5-HT<sub>2A</sub> and -HT<sub>2B</sub> receptor subtypes<ref name="pmid9225287">{{cite 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<sub>2C</sub> 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 = }}</ref>
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* SB-200,646: mixed 5-HT<sub>2B/2C</sub> antagonist
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* SB-206,553: mixed 5-HT<sub>2B/2C</sub> antagonist
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* SB-221,284: mixed 5-HT<sub>2B/2C</sub> antagonist
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* [[SB-242,084]] <ref>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</ref>
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* compound 15k: IC50 = 0.5 nM; >2000x selective over 5-HT1A, -2A, and -6, and dopamine D2–D4 receptors<ref name="pmid18602261">{{cite 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=}}</ref>
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===Inverse agonists===
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* SB-228,357: mixed 5-HT<sub>2C</sub> inverse agonist / 5-HT<sub>2B</sub> antagonist
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===Mixed response===
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* SB-243,213: high affinity, >100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and [[ion channel]]s; long duration of action in vivo (>8 h); [[anxiolytic]]-like effects.<ref name="pmid11489455">{{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<sub>2C</sub> 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 = }}</ref> ''[[Inverse agonist]]'' for the [[phospholipase A2|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 [[phospholipase C|PLC]] cascade.<ref name="pmid16807362">{{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 = }}</ref> (See also [[functional selectivity]]).
[[Categories:Receptors]]
[[Categories:Receptors]]
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==Function==
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* CNS: anxiety<ref name="pmid17451451">{{cite journal | author = Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH | title = Serotonin 5-HT<sub>2C</sub> 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 = }}</ref>
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* [[choroid plexus]]: [[cerebrospinal fluid]] (CSF) secretion<ref name="pmid14602579">{{cite journal | author = Speake T, Kibble JD, Brown PD | title = K<sub>v</sub>1.1 and K<sub>v</sub>1.3 channels contribute to the delayed-rectifying K<sup>+</sup> 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 = }}</ref>
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==External links==
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* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2324 | title = 5-HT<sub>2C</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 = }}
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==References==
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{{refbegin | 2}}
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{{PBB_Further_reading
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| citations =
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*{{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=  }}
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*{{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=  }}
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*{{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=  }}
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*{{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=  }}
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*{{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 }}
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*{{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=  }}
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*{{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=  }}
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*{{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=  }}
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*{{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 }}
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*{{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 }}
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*{{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 }}
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*{{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 }}
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*{{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 }}
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*{{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=  }}
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*{{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=  }}
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*{{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 }}
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*{{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=  }}
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*{{cite journal  | author=Backstrom JR, Price RD, Reasoner DT, Sanders-Bush E |title=Deletion of the serotonin 5-HT<sub>2C</sub> 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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}}
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{{refend}}
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{{NLM content}}
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{{transmembranereceptor-stub}}
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{{G protein-coupled receptors}}
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{{Cell signaling}}
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[[Category:G protein coupled receptors]]
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Revision as of 11:09, 16 February 2009

Contents

Description

5-hydroxytryptamine (serotonin) receptor 2C, also known as HTR2C, is a 5-HT2 receptor, but also denotes the human gene encoding it.<ref name="pmid7895773">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. PMID 7895773. </ref>

General Characterstics

Source Organism

Canis familiaris (Dog).

Taxomomy

Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae;Canis.

Subcellular Localization

Cell membrane; multi-pass membrane protein (By similarity).

Similarity

Belongs to the G-protein coupled receptor 1 family.

Post translational Modification

N-glycosylated (By similarity).

Function

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system (By similarity).

Ligands

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,<ref name="pmid17138863">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. doi:10.1124/jpet.106.113357. PMID 17138863. </ref> Ro60-0175,<ref name="pmid11399662">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. doi:10.1038/sj.bjp.0704082. PMID 11399662. </ref> mesulergine, metergoline, ritanserin, methiothepin, 5-methoxygramine, and many more.<ref name="pmid17017967">Lacivita E, Leopoldo M (2006). "Selective agents for serotonin 2C (5-HT2C) receptor". Curr Top Med Chem 6 (18): 1927–70. doi:10.2174/156802606778522168. PMID 17017967. </ref> 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

  • 1-Methylpsilocin
  • A-372,159: partial agonist, Ki 3nM, 100x selectivity over 5-HT2B
  • CP-809,101
  • Lorcaserin: full agonist, fair selectivity profile<ref name="pmid18252809">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.. doi:10.1124/jpet.107.133348. PMID 18252809. </ref><ref name="pmid15713408">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. doi:10.1016/j.bmcl.2004.12.080. PMID 15713408. </ref><ref name="pmid18039773">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. doi:10.1210/en.2007-1321. PMID 18039773. </ref>
  • MK-212
  • Ro60-0175
  • Vabicaserin
  • WAY-629<ref>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</ref>
  • WAY-161,503
  • YM-348: potent, full agonist, high affinity, high functional selectivity, orally active<ref name="pmid14709324">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. doi:10.1016/j.ejphar.2003.10.004. PMID 14709324. </ref><ref name="pmid18035544">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. doi:10.1016/j.bmc.2007.10.100. PMID 18035544. </ref>
  • (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<ref name="pmid16361098">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. doi:10.1016/j.bmcl.2005.11.083. PMID 16361098. </ref>
  • (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<ref name="pmid17315987">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. doi:10.1021/jm0612968. PMID 17315987. </ref>

Antagonists

  • FR-260,010: high affinity, selective over 5-HT2A and many other receptors; orally active.<ref name="pmid17074317">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. doi:10.1016/j.ejphar.2006.09.042. PMID 17074317. </ref>
  • RS-102,221: 100-fold selectivity compared to the 5-HT2A and -HT2B receptor subtypes<ref name="pmid9225287">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. doi:10.1016/S0028-3908(97)00049-X. PMID 9225287. </ref>
  • SB-200,646: mixed 5-HT2B/2C antagonist
  • SB-206,553: mixed 5-HT2B/2C antagonist
  • SB-221,284: mixed 5-HT2B/2C antagonist
  • SB-242,084 <ref>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</ref>
  • compound 15k: IC50 = 0.5 nM; >2000x selective over 5-HT1A, -2A, and -6, and dopamine D2–D4 receptors<ref name="pmid18602261">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. doi:10.1016/j.bmcl.2008.06.064. PMID 18602261. </ref>

Inverse agonists

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


Mixed response

  • 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.<ref name="pmid11489455">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. doi:10.1016/S0028-3908(01)00054-5. PMID 11489455. </ref> 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.<ref name="pmid16807362">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. doi:10.1124/jpet.106.104448. PMID 16807362. </ref> (See also functional selectivity).

Categories:Receptors

Function

External links

References

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