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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.
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.
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]
The non-selective serotonin receptor agonist meta-chlorophenylpiperazine (mCPP) induces migraines and this may be due to serotonin 5-HT2B receptor agonism.[26] Serotonin 5-HT2 receptor antagonists used as antimigraine agents, such as methysergide, cyproheptadine, and pizotifen, may be producing their antimigraine effects specifically via serotonin 5-HT2B receptor antagonism.[26]
The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[27] 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.[28]
6-APB – ~100-fold selectivity over the 5-HT2A and 5-HT2C receptors, ≥32-fold selectivity over monoamine release, ~12-fold selectivity over α2C-adrenergic receptor[31][38]
BW-723C86 – 100-fold selectivity over 5-HT2A but only 3- to 10-fold selectivity over 5-HT2C,[35][40] fair functional subtype selectivity, almost full agonist, anxiolytic in vivo[41]
LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[42]
VU6067416 – modest selectivity over 5-HT2A and 5-HT2C[43]
RQ-00310941 (RQ-941) – Ki = 2.0nM, IC50 = 17nM, >2,000-fold selectivity against >60 targets, under development for medical use[75][88][89]
RS-127,445 (MT-500) – Ki = 0.3nM, >1,000-fold selectivity over 5-HT2A and 5-HT2C and numerous other targets, selective over at least eight other serotonin receptors, developed for clinical use but discontinued[75][35][77][90][68]
SB-204,741 – >135-fold selectivity over 5-HT2C and 5-HT2A[91]
BW-501C67 and xylamidine are known peripherally selective antagonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A and 5-HT2B receptors, but their serotonin 5-HT2B receptor interactions do not appear to have been described.[128][129][130]
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.[131] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[132][133] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[134] 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. Bibcode:2008EToxP..60..253E. 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.
^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.
^ abSegelcke D, Messlinger K (April 2017). "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia. 37 (4): 365–371. doi:10.1177/0333102416646760. PMID27127104.
^Amemiya N, Hatta S, Takemura H, Ohshika H (December 1996). "Characterization of the contractile response induced by 5-methoxytryptamine in rat stomach fundus strips". Eur J Pharmacol. 318 (2–3): 403–409. doi:10.1016/s0014-2999(96)00777-7. PMID9016931.
^ abcTagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease". J Psychopharmacol. 37 (9): 876–890. doi:10.1177/02698811231190865. PMID37572027.
^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.
^ abBarcelo B, Gomila I (2017). "Pharmacology and Literature Review Based on Related Death and Non-Fatal Case Reports of the Benzofurans and Benzodifurans Designer Drugs". Curr Pharm Des. 23 (36): 5523–5529. doi:10.2174/1381612823666170714155140. PMID28714411.
^ abcShimshoni JA, Winkler I, Golan E, Nutt D (January 2017). "Neurochemical binding profiles of novel indole and benzofuran MDMA analogues". Naunyn Schmiedebergs Arch Pharmacol. 390 (1): 15–24. doi:10.1007/s00210-016-1297-4. hdl:10044/1/43622. PMID27650729.
^Parker MA, Marona-Lewicka D, Lucaites VL, Nelson DL, Nichols DE (December 1998). "A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor". J Med Chem. 41 (26): 5148–5149. doi:10.1021/jm9803525. PMID9857084.
^Samson SL, Ezzat S (June 2014). "AACE/ACE Disease State Clinical Review: Dopamine Agonists for Hyperprolactinemia and the Risk of Cardiac Valve Disease". Endocr Pract. 20 (6): 608–616. doi:10.4158/EP14148.RA. PMID24969114. Bromocriptine was first described as a 5HT-2BR antagonist (22) but was subsequently found to have partial agonist properties (23,24). [...] Regarding bromocriptine, there was no increased incidence of valve regurgitation in PD patients on bromocriptine in the population-based study of Schade et al (33), despite the significant findings for cabergoline and pergolide. However, there is a case report implicating high doses of bromocriptine as the cause of triple valve disease in a PD patient (37), and 1 study reported a significant correlation between cumulative dose of bromocriptine and the risk of valve regurgitation in a PD cohort (38). Other publications have reported fibrotic events, including retroperitoneal, pericardial and pleural fibrosis, in PD patients on high-dose bromocriptine (39-43). [...] Although there seems to be a lower risk of valvulopathy with bromocriptine, as a partial 5HT-2BR agonist, there still appears to be some risk with high-dose bromocriptine in PD patients.
^ abcdefgCavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". J Pharmacol Toxicol Methods. 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. PMID24361689.
^Varty GB, Canal CE, Mueller TA, Hartsel JA, Tyagi R, Avery K, et al. (April 2024). "Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist". Journal of Medicinal Chemistry. 67 (8): 6144–6188. doi:10.1021/acs.jmedchem.3c01961. PMID38593423.
^Nistala P (2018). 5-HT2B Receptor-mediated Cardiac Valvulopathy (Master of Science thesis). Virginia Commonwealth University. doi:10.25772/0YNR-6690 – via VCU Theses and Dissertations.
^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.
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^Kim M, Truss M, Pagare PP, Essandoh MA, Zhang Y, Williams DA (November 2020). "Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold". Bioorg Med Chem Lett. 30 (21): 127511. doi:10.1016/j.bmcl.2020.127511. PMID32853682.{{cite journal}}: CS1 maint: article number as page number (link)
^ abcdefgBrea J, Castro-Palomino J, Yeste S, Cubero E, Párraga A, Domínguez E, et al. (2010). "Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors". Curr Top Med Chem. 10 (5): 493–503. doi:10.2174/156802610791111524. PMID20166944.
^ abSchmitz B, Ullmer C, Segelcke D, Gwarek M, Zhu XR, Lübbert H (March 2015). "BF-1--a novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs". Eur J Pharmacol. 751: 73–80. doi:10.1016/j.ejphar.2015.01.043. PMID25666387.
^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". Cardiovasc Drugs Ther. 17 (5–6): 427–434. doi:10.1023/b:card.0000015857.96371.43. PMID15107597.
^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.
^ abcGlennon RA, Dukat M (2012). "Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission". Foye's Textbook of Medical Chemistry(PDF) (7 ed.). Baltimore: Williams and Wilkins Inc. pp. 315–337. ISBN9781609133450.
^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.
^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): 766–776. doi:10.1124/jpet.108.146514. PMID19050173. S2CID206500076.
^Odagaki Y, Kinoshita M, Ota T (September 2016). "Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes". J Psychopharmacol. 30 (9): 896–912. doi:10.1177/0269881116658989. PMID27464743.
^Tosh DK, Pavan M, Clark AA, Lammers J, Villano S, Marri S, Sgambellone S, Choi S, Lee J, Ivancich MS, Bock HA, Campbell RG, Lewicki SA, Levitan IM, Chen E, Liu N, Demby T, Gavrilova O, Gao ZG, Lucarini L, McCorvy JD, Jacobson KA. Potent and Selective Human 5-HT2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity. J Med Chem. 2024 Dec 12;67(23):21264-21291. doi:10.1021/acs.jmedchem.4c02174PMID39589936
^Rashid M, Manivet P, Nishio H, Pratuangdejkul J, Rajab M, Ishiguro M, et al. (May 2003). "Identification of the binding sites and selectivity of sarpogrelate, a novel 5-HT2 antagonist, to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling". Life Sci. 73 (2): 193–207. doi:10.1016/s0024-3205(03)00227-3. PMID12738034.
^Muntasir HA, Hossain M, Bhuiyan MA, Komiyama T, Nakamura T, Ozaki M, et al. (July 2007). "Identification of a key amino acid of the human 5-HT(2B) serotonin receptor important for sarpogrelate binding". J Pharmacol Sci. 104 (3): 274–277. doi:10.1254/jphs.sc0060241. PMID17609583.
^Yoon J, Choi WI, Lee WH, Lee GB, Choi BW, Kim P, et al. (March 2025). "Synthesis and Biological Evaluation of Peripheral 5HT2B Antagonists for Liver Fibrosis". J Med Chem. 68 (6): 6493–6506. doi:10.1021/acs.jmedchem.4c03003. PMID40048549.
^Chaouloff F, Layeillon C, Baudrie V (January 1993). "5-HT1C/5-HT2 receptor blockade prevents 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane-, but not stress-induced increases in brain tryptophan". European Journal of Pharmacology. 231 (1): 77–82. doi:10.1016/0014-2999(93)90686-c. PMID8095238.
^Glennon RA, Westkaemper RB (1992). "Serotonin Receptors, 5-th Ligands and Receptor Modeling". Pharmacochemistry Library. Vol. 18. Elsevier. pp. 185–207. doi:10.1016/b978-0-444-88931-7.50017-7. ISBN978-0-444-88931-7. Various polycyclic agents such as butaclamol, mianserin, cyproheptadine, pizotyline bind at 5-HT2 receptors with high affinity. These agents are not selective and bind with comparable affinty either at other populations of 5-HT receptors or at other neurotransmitter receptors. Other, structurally unique agents have also been investigated including cinanserin and xylamidine. The latter compound has seen application as a peripheral 5-HT2 antagonist in that it does not readily penetrate the blood-brain barrier; however, xylamidine binds equally well at 5-HTIC and 5-HT2 receptors. See references 3 and 5 for additional information on these types of agents.
^Dave KD, Quinn JL, Harvey JA, Aloyo VJ (March 2004). "Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit". Pharmacol Biochem Behav. 77 (3): 623–629. doi:10.1016/j.pbb.2003.12.017. PMID15006475. Systemic administration of the peripheral 5-HT2A/2C antagonist xylamidine [...] First, systemic injections of the peripherally acting 5-HT2A/2C receptor antagonist xylamidine were employed to study its effects on head bobs and body shakes produced by systemic injections of DOI.
^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.
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"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.
