5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2Bgene.[5][6] 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitterserotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.
Tissue distribution and function
First discovered in the stomach of rats, 5-HT2B was challenging to characterize initially because of its structural similarity to the other 5-HT2 receptors, particularly 5-HT2C.[7] 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 (CNS) effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenicsubstituted amphetamines. The 5-HT2B receptor is expressed in several areas of the CNS, including the dorsal hypothalamus, frontal cortex, medial amygdala, and meninges.[8] However, its most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.[9]
The 5-HT2B receptor subtype is involved in:
CNS: inhibition of serotonin and dopamine uptake, behavioral effects[10]
Cardiac: The 5-HT2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice.[12] Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts,[13] with chronic overstimulation leading to valvulopathy.[14][15] These receptors are also overexpressed in human failing heart and antagonists of 5-HT2B receptors were discovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.[16][17][18]
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,[19] and with the abnormal acute serotonin release produced by drugs such as MDMA.[10] Surprisingly, however, 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels,[20] despite its role in modulating serotonin release.
Clinical significance
5-HT2B receptors have been strongly implicated in causing drug-induced valvular heart disease.[21][22][23] The Fen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT2B stimulation.[24] Today, 5-HT2B agonism is considered a toxicity signal precluding further clinical development of a compound.[25]
Ligands
The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[26] 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.[27]
Agonists
Selective
BW-723C86[28] – fair functional subtype selectivity; almost full agonist. Anxiolytic in vivo[29]
Ro60-0175[28] – functionally selective over 5-HT2A, potent agonist at both 5-HT2B/C
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.[47] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[48][49] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[50] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.
^Elangbam CS, Job LE, Zadrozny LM, Barton JC, Yoon LW, Gates LD, et al. (Aug 2008). "5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats". Experimental and Toxicologic Pathology. 60 (4–5): 253–62. doi:10.1016/j.etp.2008.03.005. PMID18511249.
^Padhariya K, Bhandare R, Canney D, Velingkar V (2017-12-12). "Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists". Cardiovascular & Hematological Disorders Drug Targets. 17 (2): 86–104. doi:10.2174/1871529X17666170703115111. PMID28676029.
^Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, et al. (Jan 2000). "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Molecular Pharmacology. 57 (1): 75–81. PMID10617681.
^Roth BL (Jan 2007). "Drugs and valvular heart disease". The New England Journal of Medicine. 356 (1): 6–9. doi:10.1056/NEJMp068265. PMID17202450.
^Cavero I, Guillon JM (2014-03-01). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". Journal of Pharmacological and Toxicological Methods. 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. PMID24361689.
^Kennett GA, Trail B, Bright F (Dec 1998). "Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated". Neuropharmacology. 37 (12): 1603–10. doi:10.1016/S0028-3908(98)00115-4. PMID9886683. S2CID7310462.
^Görnemann T, Hübner H, Gmeiner P, Horowski R, Latté KP, Flieger M, et al. (Mar 2008). "Characterization of the molecular fragment that is responsible for agonism of pergolide at serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A receptors". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 1136–45. doi:10.1124/jpet.107.133165. PMID18096760. S2CID24907300.
^Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, et al. (Sep 2003). "The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways". The Journal of Pharmacology and Experimental Therapeutics. 306 (3): 954–64. doi:10.1124/jpet.103.051797. PMID12750432. S2CID18753440.
^Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, et al. (2006). "Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis". Clinical Neuropharmacology. 29 (2): 80–6. doi:10.1097/00002826-200603000-00005. PMID16614540. S2CID33849447.
^Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M (Apr 1998). "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology. 136 (4): 409–14. doi:10.1007/s002130050585. PMID9600588. S2CID3021798.
^Kovács A, Gacsályi I, Wellmann J, Schmidt E, Szücs Z, Dubreuil V, et al. (2003). "Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist". Cardiovascular Drugs and Therapy. 17 (5–6): 427–34. doi:10.1023/B:CARD.0000015857.96371.43. PMID15107597. S2CID11532969.
^Dunlop J, Lock T, Jow B, Sitzia F, Grauer S, Jow F, et al. (Mar 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)". The Journal of Pharmacology and Experimental Therapeutics. 328 (3): 766–76. doi:10.1124/jpet.108.146514. PMID19050173. S2CID206500076.
^Poissonnet G, Parmentier JG, Boutin JA, Goldstein S (Mar 2004). "The emergence of selective 5-HT 2B antagonists structures, activities and potential therapeutic applications". Mini Reviews in Medicinal Chemistry. 4 (3): 325–30. doi:10.2174/1389557043487312. PMID15032678.
^Shyu KG (Jan 2009). "Serotonin 5-HT2B receptor in cardiac fibroblast contributes to cardiac hypertrophy: a new therapeutic target for heart failure?". Circulation Research. 104 (1): 1–3. doi:10.1161/CIRCRESAHA.108.191122. PMID19118279. S2CID41931843.
^Moss N, Choi Y, Cogan D, Flegg A, Kahrs A, Loke P, et al. (Apr 2009). "A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2206–10. doi:10.1016/j.bmcl.2009.02.126. PMID19307114.
Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacology & Therapeutics. 92 (2–3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID11916537.
Choi DS, Birraux G, Launay JM, Maroteaux L (Oct 1994). "The human serotonin 5-HT2B receptor: pharmacological link between 5-HT2 and 5-HT1D receptors". FEBS Letters. 352 (3): 393–9. doi:10.1016/0014-5793(94)00968-6. PMID7926008. S2CID26931598.
Kursar JD, Nelson DL, Wainscott DB, Baez M (Aug 1994). "Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor". Molecular Pharmacology. 46 (2): 227–34. PMID8078486.
Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, et al. (May 2003). "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways". Oncogene. 22 (21): 3307–18. doi:10.1038/sj.onc.1206406. PMID12761501. S2CID38880905.
Lin Z, Walther D, Yu XY, Drgon T, Uhl GR (Dec 2004). "The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse". Pharmacogenetics. 14 (12): 805–11. doi:10.1097/00008571-200412000-00003. PMID15608559.
External links
"5-HT2B". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2017-02-02. Retrieved 2008-11-25.
