The 5-HT2 receptors (of which the 5-HT2B receptor is a subtype) mediate many of the central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets; central nervous system effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenicsubstituted amphetamines.
Cardiac: The 5-HT2B receptor regulates cardiac structure and functions as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice. The 5-HT2B receptor stimulation can also lead to pathological proliferation of cardiac valves fibroblasts, which with chronic overstimulation of 5-HT2B can lead to a severe valvulopathy. Moreover, 5-HT2B receptors were recently shown to be overexpressed in human failing heart and antagonists of 5-HT2B receptors were uncovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.
Serotonin transporter: 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA. Surprisingly however 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels, despite its role in modulating serotonin release.
As of 2009, few highly selective 5-HT2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT2B agonists, and the lack of clear therapeutic application for 5-HT2B antagonists, but there is still a need for selective ligands for scientific research.
5-HT2B antagonists have previously been proposed as treatment for migraine headaches, and RS-127,445 was trialled in humans up to Phase I for this indication, but development was not continued. More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease. Serotonin 5-HT2B receptors inhibit liver regeneration.
^ abDoly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (March 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". J. Neurosci.28 (11): 2933–40. doi:10.1523/JNEUROSCI.5723-07.2008. PMID18337424.
^Launay JM, Hervé P, Peoc'h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G, Maroteaux L (October 2002). "Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension". Nat. Med.8 (10): 1129–35. doi:10.1038/nm764. PMID12244304.
^Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, Slocum N (August 2008). "5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats". Exp. Toxicol. Pathol.60 (4–5): 253–62. doi:10.1016/j.etp.2008.03.005. PMID18511249.
^Jaffré F, Callebert J, Sarre A, Etienne N, Nebigil CG, Launay JM, Maroteaux L, Monassier L (August 2004). "Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts". Circulation110 (8): 969–74. doi:10.1161/01.CIR.0000139856.20505.57. PMID15302781.
^Callebert J, Esteve JM, Hervé P, Peoc'h K, Tournois C, Drouet L, Launay JM, Maroteaux L (May 2006). "Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice". J. Pharmacol. Exp. Ther.317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID16461587.
^Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation102 (23): 2836–41. doi:10.1161/01.CIR.102.23.2836. PMID11104741.
^Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW (January 2000). "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Mol. Pharmacol.57 (1): 75–81. PMID10617681.
^Kennett GA, Trail B, Bright F (December 1998). "Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated". Neuropharmacology37 (12): 1603–10. doi:10.1016/S0028-3908(98)00115-4. PMID9886683.
^Görnemann T, Hübner H, Gmeiner P, et al. (2008). "Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors". J. Pharmacol. Exp. Ther.324 (3): 1136–45. doi:10.1124/jpet.107.133165. PMID18096760.
^Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M (April 1998). "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology (Berl.)136 (4): 409–14. doi:10.1007/s002130050585. PMID9600588.
^Dunlop J, Lock T, Jow B, et al. (March 2009). "Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide)". J. Pharmacol. Exp. Ther.328 (3): 766–76. doi:10.1124/jpet.108.146514. PMID19050173.
^Poissonnet G, Parmentier JG, Boutin JA, Goldstein S (March 2004). "The emergence of selective 5-HT 2B antagonists structures, activities and potential therapeutic applications". Mini Rev Med Chem4 (3): 325–30. doi:10.2174/1389557043487312. PMID15032678.
^Shyu KG (January 2009). "Serotonin 5-HT2B receptor in cardiac fibroblast contributes to cardiac hypertrophy: a new therapeutic target for heart failure?". Circulation Research104 (1): 1–3. doi:10.1161/CIRCRESAHA.108.191122. PMID19118279.
^Moss N, Choi Y, Cogan D, Flegg A, Kahrs A, Loke P, Meyn O, Nagaraja R, Napier S, Parker A, Thomas Peterson J, Ramsden P, Sarko C, Skow D, Tomlinson J, Tye H, Whitaker M (April 2009). "A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties". Bioorganic & Medicinal Chemistry Letters19 (8): 2206–10. doi:10.1016/j.bmcl.2009.02.126. PMID19307114.
Choi DS, Birraux G, Launay JM, Maroteaux L (1994). "The human serotonin 5-HT2B receptor: pharmacological link between 5-HT2 and 5-HT1D receptors". FEBS Lett.352 (3): 393–9. doi:10.1016/0014-5793(94)00968-6. PMID7926008.
Kursar JD, Nelson DL, Wainscott DB, Baez M (1994). "Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor". Mol. Pharmacol.46 (2): 227–34. PMID8078486.
Kim SJ, Veenstra-VanderWeele J, Hanna GL, et al. (2000). "Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder". Mol. Cell. Probes14 (1): 47–52. doi:10.1006/mcpr.1999.0281. PMID10722792.
Manivet P, Mouillet-Richard S, Callebert J, et al. (2000). "PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor". J. Biol. Chem.275 (13): 9324–31. doi:10.1074/jbc.275.13.9324. PMID10734074.
Becamel C, Figge A, Poliak S, et al. (2001). "Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1". J. Biol. Chem.276 (16): 12974–82. doi:10.1074/jbc.M008089200. PMID11150294.
Manivet P, Schneider B, Smith JC, et al. (2002). "The serotonin binding site of human and murine 5-HT2B receptors: molecular modeling and site-directed mutagenesis". J. Biol. Chem.277 (19): 17170–8. doi:10.1074/jbc.M200195200. PMID11859080.
Matsuda A, Suzuki Y, Honda G, et al. (2003). "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways". Oncogene22 (21): 3307–18. doi:10.1038/sj.onc.1206406. PMID12761501.
Slominski A, Pisarchik A, Zbytek B, et al. (2003). "Functional activity of serotoninergic and melatoninergic systems expressed in the skin". J. Cell. Physiol.196 (1): 144–53. doi:10.1002/jcp.10287. PMID12767050.
Lin Z, Walther D, Yu XY, et al. (2005). "The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse". Pharmacogenetics14 (12): 805–11. doi:10.1097/00008571-200412000-00003. PMID15608559.
Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature434 (7034): 724–31. doi:10.1038/nature03466. PMID15815621.