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| | ==Description== | | ==Description== |
| - | '''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> | + | '''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, |
| - | ==General Characterstics==
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| - | ===Source Organism===
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| - | Canis familiaris (Dog).
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| - | ===Taxomomy===
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| - | Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae;Canis.
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| - | ===Subcellular Localization===
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| - | Cell membrane; multi-pass membrane protein (By similarity).
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| - | ===Similarity===
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| - | Belongs to the G-protein coupled receptor 1 family.
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| - | ===Post translational Modification===
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| - | N-glycosylated (By similarity).
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| - | ==Function==
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| - | 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]]).
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| - | [[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== | | ==External links== |
| | * {{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 = }} | | * {{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 = }} |
