5-hydroxytryptamine 2C receptor

From DrugPedia: A Wikipedia for Drug discovery

[edit] 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-HT_2C receptor". Eur. J. Pharmacol. 269 (3): 339–48. PMID 7895773. </ref>

[edit] General Characterstics

[edit] Source Organism

Canis familiaris (Dog).

[edit] Taxomomy

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

[edit] Subcellular Localization

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

[edit] Similarity

Belongs to the G-protein coupled receptor 1 family.

[edit] Post translational Modification

N-glycosylated (By similarity).

[edit] 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,<ref name="pmid17138863">Hackler EA, Turner GH, Gresch PJ, Sengupta S, Deutch AY, Avison MJ, Gore JC, Sanders-Bush E (2007). "5-Hydroxytryptamine_2C 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-HT_2C) 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-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.

[edit] Agonists

1-Methylpsilocin
A-372,159: partial agonist, Ki 3nM, 100x selectivity over 5-HT_2B
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-HT_2C 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-HT_2C 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-HT_2C 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-HT_2C 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-HT_2C 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-HT_2B and >70-fold over 5-HT_2A<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-HT_2C receptor". J. Med. Chem. 50 (6): 1365–79. doi:10.1021/jm0612968. PMID 17315987. </ref>

[edit] Antagonists

FR-260,010: high affinity, selective over 5-HT_2A 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-HT_2C 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-HT_2A and -HT_2B 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-HT_2C receptor antagonist". Neuropharmacology 36 (4-5): 621–9. doi:10.1016/S0028-3908(97)00049-X. PMID 9225287. </ref>

SB-200,646: mixed 5-HT_2B/2C antagonist

SB-206,553: mixed 5-HT_2B/2C antagonist

SB-221,284: mixed 5-HT_2B/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>

[edit] Inverse agonists

SB-228,357: mixed 5-HT_2C inverse agonist / 5-HT_2B antagonist

[edit] 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-HT_2C 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).

[edit] ]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)