Biology:5-HT2B receptor

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene.[1][2] 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (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.[3] 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 hallucinogenic substituted amphetamines. The 5-HT2B receptor is expressed in several areas of the CNS, including the dorsal hypothalamus, frontal cortex, medial amygdala, and meninges.[4] However, its most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.[5]

The 5-HT2B receptor subtype is involved in:

  • CNS: inhibition of serotonin and dopamine uptake, behavioral effects[6]
  • Vascular: pulmonary vasoconstriction[7]
  • Cardiac: The 5-HT2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice.[8] Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts,[9] with chronic overstimulation leading to valvulopathy.[10][11] 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.[12][13][14]
  • 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,[15] and with the abnormal acute serotonin release produced by drugs such as MDMA.[6] Surprisingly, however, 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels,[16] despite its role in modulating serotonin release.

Clinical significance

Valvular heart disease

5-HT2B receptors have been strongly implicated in causing drug-induced valvular heart disease.[17][18][19] The Fen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT2B stimulation.[20] Today, 5-HT2B agonism is considered a toxicity signal precluding further clinical development of a compound.[21]

Migraines

The non-selective serotonin receptor agonist meta-chlorophenylpiperazine (mCPP) induces migraines and this may be due to serotonin 5-HT2B receptor agonism.[22] 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.[22]

Ligands

The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[23] 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.[24]

Agonists

Endogenous

Selective

  • 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[27][34]
  • α-Methylserotonin – ~10-fold selectivity over 5-HT2A and 5-HT2C[31][35][33]
  • BW-723C86 – 100-fold selectivity over 5-HT2A but only 3- to 10-fold selectivity over 5-HT2C,[31][36] fair functional subtype selectivity, almost full agonist, anxiolytic in vivo[37]
  • LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[38]
  • VU6067416 – modest selectivity over 5-HT2A and 5-HT2C[39]

Non-selective

Peripherally selective

Inactive

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT2B receptor agonists, at least in vitro.[27] These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others.[27][44][34][68][69][70] Findings are somewhat conflicting for certain psychedelics, such as psilocin and LSD, but most studies find that these drugs are indeed potent serotonin 5-HT2B receptor agonists.[60][27][29]

Antagonists

Selective

  • 5-HCPC[71][72]
  • 5-HPEC (weak)[71]
  • 5-HPPC[71]
  • AM1125[71]
  • AM1476[71]
  • BF-1 – derived from pimethixene[71][73][74]
  • EGIS-7625 – high selectivity over 5-HT2A[73][75][76]
  • EXT5 – highly selective[71][77]
  • EXT9 – somewhat selective[71][77]
  • LY-23,728[78]
  • LY-266,097 – pKi = 9.7, 100-fold selectivity over 5-HT2A and 5-HT2C[31][78]
  • LY-272,015 – fairly selective and highly potent[31]
  • LY-287,375[78][79]
  • MRS7925 – substantially selective over 5-HT2A and 5-HT2C but minimal selectivity over the adenosine A1 receptor[80]
  • MRS8209[81]
  • MW071 (MW01-8-071HAB) – non-MAOI minaprine analogue[82]
  • MW073 – highly selective, orally bioavailable[83]
  • PRX-08066 – Ki ≈ 1.7 nM, >100-fold selectivity[71][73][31]
  • RQ-00310941 (RQ-941) – Ki = 2.0 nM, IC50 = 17 nM, >2,000-fold selectivity against >60 targets, under development for medical use[71][84][85]
  • RS-127,445 (MT-500) – Ki = 0.3 nM, >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[71][31][73][86][64]
  • SB-204,741 – >135-fold selectivity over 5-HT2C and 5-HT2A[87]
  • SB-215,505 – mixed 5-HT2B and 5-HT2C antagonist[31][73][88]
  • VU6047534 – weak partial agonist or antagonist, peripherally selective in mice but not humans[89][90]

Non-selective

Unknown or unsorted selectivity

Peripherally selective

  • MRS8209[119]
  • Sarpogrelate (MCI-9042, LS-187,118) – non-selective 5-HT2 antagonist, but ~2 orders of magnitude lower affinity at 5-HT2B than at 5-HT2A[120][121]
  • VU0530244 – 5-HT2B-selective[122]
  • VU0631019 – 5-HT2B-selective[122]
  • VU6055320 – 5-HT2B-selective[89][90]
  • Others (e.g., "compound 19c")[123]

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.[124][125][126]

Possible applications

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.[127] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[128][129] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[130] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.

See also

References

  1. ↑ "Entrez Gene: HTR2B 5-hydroxytryptamine (serotonin) receptor 2B". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3357. 
  2. ↑ "Cloning and functional characterization of the human 5-HT2B serotonin receptor". FEBS Letters 342 (1): 85–90. Mar 1994. doi:10.1016/0014-5793(94)80590-3. PMID 8143856. Bibcode: 1994FEBSL.342...85S. 
  3. ↑ "Serotonin" (in en). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincott-Raven. 1999. https://www.ncbi.nlm.nih.gov/books/NBK28150/. 
  4. ↑ "The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors". British Journal of Pharmacology 115 (4): 622–8. June 1995. doi:10.1111/j.1476-5381.1995.tb14977.x. PMID 7582481. 
  5. ↑ XPharm: the comprehensive pharmacology reference. Amsterdam: Elsevier. 2008. ISBN 978-0-08-055232-3. OCLC 712018683. 
  6. ↑ 6.0 6.1 "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". The Journal of Neuroscience 28 (11): 2933–40. Mar 2008. doi:10.1523/JNEUROSCI.5723-07.2008. PMID 18337424. 
  7. ↑ "Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension". Nature Medicine 8 (10): 1129–35. Oct 2002. doi:10.1038/nm764. PMID 12244304. https://hal.archives-ouvertes.fr/hal-01985063/file/NM_final_rev.pdf. 
  8. ↑ "Ablation of serotonin 5-HT(2B) receptors in mice leads to abnormal cardiac structure and function". Circulation 103 (24): 2973–9. Jun 2001. doi:10.1161/01.cir.103.24.2973. PMID 11413089. 
  9. ↑ "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. Aug 2008. doi:10.1016/j.etp.2008.03.005. PMID 18511249. Bibcode: 2008EToxP..60..253E. 
  10. ↑ "Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists". Cardiovascular & Hematological Disorders Drug Targets 17 (2): 86–104. 2017-12-12. doi:10.2174/1871529X17666170703115111. PMID 28676029. 
  11. ↑ "Serotonin—pain modulation". Handbook of the Behavioral Neurobiology of Serotonin. Handbook of Behavioral Neuroscience. 31. Elsevier. 2020. pp. 309–320. doi:10.1016/b978-0-444-64125-0.00017-7. ISBN 978-0-444-64125-0. 
  12. ↑ "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". Circulation 110 (8): 969–74. Aug 2004. doi:10.1161/01.CIR.0000139856.20505.57. PMID 15302781. 
  13. ↑ "Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice". Hypertension 52 (2): 301–7. Aug 2008. doi:10.1161/HYPERTENSIONAHA.107.105551. PMID 18591460. 
  14. ↑ "Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy". Circulation Research 104 (1): 113–23. Jan 2009. doi:10.1161/CIRCRESAHA.108.180976. PMID 19023134. 
  15. ↑ "Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice". The Journal of Pharmacology and Experimental Therapeutics 317 (2): 724–31. May 2006. doi:10.1124/jpet.105.098269. PMID 16461587. https://hal.archives-ouvertes.fr/hal-01274937/file/Callebert0206.pdf. 
  16. ↑ "Implication of 5-HT(2B) receptors in the serotonin syndrome". Neuropharmacology 61 (3): 495–502. Sep 2011. doi:10.1016/j.neuropharm.2011.01.025. PMID 21277875. http://www.hal.inserm.fr/inserm-00561473. 
  17. ↑ "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation 102 (23): 2836–41. Dec 2000. doi:10.1161/01.CIR.102.23.2836. PMID 11104741. 
  18. ↑ "Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine". Molecular Pharmacology 57 (1): 75–81. Jan 2000. doi:10.1016/S0026-895X(24)26444-0. PMID 10617681. 
  19. ↑ "Drugs and valvular heart disease". The New England Journal of Medicine 356 (1): 6–9. Jan 2007. doi:10.1056/NEJMp068265. PMID 17202450. 
  20. ↑ "Archive: How Fen-Phen, a Diet 'Miracle,' Rose and Fell". https://archive.nytimes.com/www.nytimes.com/partners/aol/special/women/warchive/970923_1080.html. 
  21. ↑ "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. 2014-03-01. doi:10.1016/j.vascn.2013.12.004. PMID 24361689. 
  22. ↑ 22.0 22.1 "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia 37 (4): 365–371. April 2017. doi:10.1177/0333102416646760. PMID 27127104. https://nbn-resolving.org/urn:nbn:de:bvb:29-opus4-112198. 
  23. ↑ PDB: 4IB4​; "Structural features for functional selectivity at serotonin receptors". Science 340 (6132): 615–9. May 2013. doi:10.1126/science.1232808. PMID 23519215. Bibcode: 2013Sci...340..615W. 
  24. ↑ Schuhmacher M (2007). [Chiral arylmethoxytryptamines as 5-HT2B-receptor antagonists: synthesis, analysis and in-vitro pharmacology] (German) (PDF) (Thesis). Ph.D. Dissertation. University of Regensburg. pp. 6–17. Archived from the original (PDF) on 2011-07-18. Retrieved 2008-08-11.
  25. ↑ "Characterization of the contractile response induced by 5-methoxytryptamine in rat stomach fundus strips". Eur J Pharmacol 318 (2–3): 403–409. December 1996. doi:10.1016/s0014-2999(96)00777-7. PMID 9016931. 
  26. ↑ "Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle". Br J Pharmacol 112 (1): 323–331. May 1994. doi:10.1111/j.1476-5381.1994.tb13072.x. PMID 8032658. 
  27. ↑ 27.00 27.01 27.02 27.03 27.04 27.05 27.06 27.07 27.08 27.09 27.10 27.11 27.12 27.13 27.14 27.15 27.16 27.17 27.18 27.19 27.20 27.21 27.22 27.23 27.24 "Drugs of Abuse Affecting 5-HT2B Receptors". 5-HT2B Receptors. The Receptors. 35. Cham: Springer International Publishing. 2021. pp. 277–289. doi:10.1007/978-3-030-55920-5_16. ISBN 978-3-030-55919-9. 
  28. ↑ "Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT)". ACS Chem Neurosci 9 (10): 2344–2357. October 2018. doi:10.1021/acschemneuro.8b00101. PMID 30036036. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 "Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens". Eur Neuropsychopharmacol 26 (8): 1327–1337. August 2016. doi:10.1016/j.euroneuro.2016.05.001. PMID 27216487. http://edoc.unibas.ch/53326/1/20170117174852_587e4af45b658.pdf. 
  30. ↑ 30.0 30.1 30.2 "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease". J Psychopharmacol 37 (9): 876–890. September 2023. doi:10.1177/02698811231190865. PMID 37572027. 
  31. ↑ 31.00 31.01 31.02 31.03 31.04 31.05 31.06 31.07 31.08 31.09 31.10 31.11 31.12 31.13 31.14 31.15 31.16 31.17 31.18 Hall FS, ed (2013). "Contribution of Serotonin 5-HT2B Receptors to Health and Disease". Serotonin: Biosynthesis, Regulation and Health Implications. New York: Nova Science Publishers. ISBN 978-1-62417-636-4. https://www.researchgate.net/publication/289784161. 
  32. ↑ 32.00 32.01 32.02 32.03 32.04 32.05 32.06 32.07 32.08 32.09 32.10 32.11 32.12 32.13 32.14 "Serotonin receptors and heart valve disease--it was meant 2B". Pharmacol Ther 132 (2): 146–157. November 2011. doi:10.1016/j.pharmthera.2011.03.008. PMID 21440001. 
  33. ↑ 33.00 33.01 33.02 33.03 33.04 33.05 33.06 33.07 33.08 33.09 "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". Br J Pharmacol 128 (1): 13–20. September 1999. doi:10.1038/sj.bjp.0702751. PMID 10498829. 
  34. ↑ 34.0 34.1 34.2 34.3 "Neurochemical profiles of some novel psychoactive substances". Eur J Pharmacol 700 (1–3): 147–151. January 2013. doi:10.1016/j.ejphar.2012.12.006. PMID 23261499. 
  35. ↑ 35.0 35.1 "Serotonin receptors nomenclature". The Serotonin System. Elsevier. 2019. pp. 63–93. doi:10.1016/b978-0-12-813323-1.00004-9. ISBN 978-0-12-813323-1. https://www.researchgate.net/publication/333937933. 
  36. ↑ 36.0 36.1 36.2 "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". British Journal of Pharmacology 128 (1): 13–20. Sep 1999. doi:10.1038/sj.bjp.0702751. PMID 10498829. 
  37. ↑ "Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated". Neuropharmacology 37 (12): 1603–10. Dec 1998. doi:10.1016/S0028-3908(98)00115-4. PMID 9886683. 
  38. ↑ "Structural determinants of 5-HT2B receptor activation and biased agonism". Nature Structural & Molecular Biology 25 (9): 787–796. August 2018. doi:10.1038/s41594-018-0116-7. PMID 30127358. 
  39. ↑ 39.0 39.1 "Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.". ACS Medicinal Chemistry Letters 15 (2): 302–309. January 2024. doi:10.1021/acsmedchemlett.3c00566. PMID 38352850. 
  40. ↑ 40.0 40.1 40.2 40.3 40.4 40.5 40.6 "Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)". Neuropharmacology 99: 546–553. December 2015. doi:10.1016/j.neuropharm.2015.08.034. PMID 26318099. http://edoc.unibas.ch/56163/1/20170921163006_59c3cceeb8e5d.pdf. 
  41. ↑ 41.0 41.1 "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. 2017. doi:10.2174/1381612823666170714155140. PMID 28714411. 
  42. ↑ 42.0 42.1 42.2 "Neurochemical binding profiles of novel indole and benzofuran MDMA analogues". Naunyn Schmiedebergs Arch Pharmacol 390 (1): 15–24. January 2017. doi:10.1007/s00210-016-1297-4. PMID 27650729. 
  43. ↑ "Pharmacological properties and discriminative stimulus effects of a novel and selective 5-HT2 receptor agonist AL-38022A [(S)-2-(8,9-dihydro-7H-pyrano[2,3-gindazol-1-yl)-1-methylethylamine]"]. Pharmacol Biochem Behav 91 (3): 307–314. January 2009. doi:10.1016/j.pbb.2008.07.015. PMID 18718483. 
  44. ↑ 44.0 44.1 44.2 "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  45. ↑ "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol Biochem Behav 71 (4): 825–836. April 2002. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. 
  46. ↑ "Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs". ACS Chemical Neuroscience 14 (1): 119–135. January 2023. doi:10.1021/acschemneuro.2c00597. PMID 36521179. 
  47. ↑ "Targeting the 5-HT system: Potential side effects". Neuropharmacology 179. November 2020. doi:10.1016/j.neuropharm.2020.108233. PMID 32805212. 
  48. ↑ "Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors". PLOS ONE 8 (11). 2013. doi:10.1371/journal.pone.0078515. PMID 24244317. Bibcode: 2013PLoSO...878515I. 
  49. ↑ "A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor". J Med Chem 41 (26): 5148–5149. December 1998. doi:10.1021/jm9803525. PMID 9857084. 
  50. ↑ "AACE/ACE Disease State Clinical Review: Dopamine Agonists for Hyperprolactinemia and the Risk of Cardiac Valve Disease". Endocr Pract 20 (6): 608–616. June 2014. doi:10.4158/EP14148.RA. PMID 24969114. "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.". 
  51. ↑ 51.0 51.1 51.2 51.3 51.4 51.5 51.6 "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy". J Pharmacol Toxicol Methods 69 (2): 150–161. 2014. doi:10.1016/j.vascn.2013.12.004. PMID 24361689. 
  52. ↑ "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. April 2024. doi:10.1021/acs.jmedchem.3c01961. PMID 38593423. 
  53. ↑ "ACNP 62nd Annual Meeting: Poster Abstracts P251 – P500: P405. Discovery and Preclinical Characterization of the Phenylalkylamine, CYB210010, a Potent and Long-Acting Serotonin 5-HT2A Receptor Agonist". Neuropsychopharmacology 48 (Suppl 1): 211–354 (299–299. December 2023. doi:10.1038/s41386-023-01756-4. PMID 38040810. 
  54. ↑ 54.00 54.01 54.02 54.03 54.04 54.05 54.06 54.07 54.08 54.09 "Serotonergic drugs and valvular heart disease". Expert Opin Drug Saf 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  55. ↑ 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.
  56. ↑ "Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy". Br J Pharmacol 140 (2): 277–284. September 2003. doi:10.1038/sj.bjp.0705437. PMID 12970106. 
  57. ↑ 57.0 57.1 "Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines". The FASEB Journal 36 (S1). 2022. doi:10.1096/fasebj.2022.36.S1.R2691. ISSN 0892-6638. https://www.researchgate.net/publication/360369275. 
  58. ↑ "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Molecular Pharmacology 76 (4): 710–22. Oct 2009. doi:10.1124/mol.109.058057. PMID 19570945. 
  59. ↑ 59.0 59.1 "PDSP Ki database, University of North Carolina at Chapel Hill". https://pdsp.unc.edu/databases/kidb.php. 
  60. ↑ 60.0 60.1 60.2 60.3 "Cardiovascular safety of psychedelic medicine: current status and future directions". Pharmacol Rep 75 (6): 1362–1380. December 2023. doi:10.1007/s43440-023-00539-4. PMID 37874530. 
  61. ↑ "Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775)". Drug Test Anal 10 (2): 310–322. February 2018. doi:10.1002/dta.2222. PMID 28585392. 
  62. ↑ 62.0 62.1 "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–1229. Jun 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. https://www.researchgate.net/publication/10748715. 
  63. ↑ "Psychedelics and the human receptorome". PLOS ONE 5 (2). 2010. doi:10.1371/journal.pone.0009019. PMID 20126400. Bibcode: 2010PLoSO...5.9019R. 
  64. ↑ 64.00 64.01 64.02 64.03 64.04 64.05 64.06 64.07 64.08 64.09 64.10 64.11 64.12 "Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors". Naunyn Schmiedebergs Arch Pharmacol 370 (2): 114–123. August 2004. doi:10.1007/s00210-004-0951-4. PMID 15322733. 
  65. ↑ "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". AAPS J 9 (1): E1–10. January 2007. doi:10.1208/aapsj0901001. PMID 17408232. 
  66. ↑ "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. Mar 2008. doi:10.1124/jpet.107.133165. PMID 18096760. 
  67. ↑ "AL-34662". https://drugs.ncats.io/substance/1Q6O947QMH. 
  68. ↑ "Pharmacological profile of mephedrone analogs and related new psychoactive substances". Neuropharmacology 134 (Pt A): 4–12. May 2018. doi:10.1016/j.neuropharm.2017.07.026. PMID 28755886. https://edoc.unibas.ch/57357/1/20170920120908_59c23e44b5f0e.pdf. 
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  70. ↑ "Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems". J Psychopharmacol 33 (7): 831–841. July 2019. doi:10.1177/0269881119844185. PMID 31038382. 
  71. ↑ 71.00 71.01 71.02 71.03 71.04 71.05 71.06 71.07 71.08 71.09 71.10 71.11 71.12 71.13 71.14 "Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor". Pharmaceuticals (Basel) 14 (2): 76. January 2021. doi:10.3390/ph14020076. PMID 33498477. 
  72. ↑ "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). November 2020. doi:10.1016/j.bmcl.2020.127511. PMID 32853682. 
  73. ↑ 73.0 73.1 73.2 73.3 73.4 73.5 73.6 "Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors". Curr Top Med Chem 10 (5): 493–503. 2010. doi:10.2174/156802610791111524. PMID 20166944. 
  74. ↑ 74.0 74.1 "BF-1--a novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs". Eur J Pharmacol 751: 73–80. March 2015. doi:10.1016/j.ejphar.2015.01.043. PMID 25666387. 
  75. ↑ "Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist". Cardiovasc Drugs Ther 17 (5–6): 427–434. 2003. doi:10.1023/b:card.0000015857.96371.43. PMID 15107597. 
  76. ↑ "Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist". Cardiovascular Drugs and Therapy 17 (5–6): 427–34. 2003. doi:10.1023/B:CARD.0000015857.96371.43. PMID 15107597. 
  77. ↑ 77.0 77.1 "5-HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo". Physiol Rep 4 (15). August 2016. doi:10.14814/phy2.12873. PMID 27482070. 
  78. ↑ 78.0 78.1 78.2 "Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission". Foye's Textbook of Medical Chemistry (7 ed.). Baltimore: Williams and Wilkins Inc.. 2012. pp. 315–337. ISBN 978-1-60913-345-0. https://downloads.lww.com/wolterskluwer_vitalstream_com/sample-content/9781609133450_Lemke/samples/Chapter_11.pdf. 
  79. ↑ "5-HT2A, 5-HT2B and 5-HT2C receptor ligands". Pharmacochemistry Library. 27. Elsevier. 1997. pp. 161–197. doi:10.1016/s0165-7208(97)80013-x. ISBN 978-0-444-82041-9. 
  80. ↑ "Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N6, C2 and 5'-Modified (N)-methanocarba-adenosine derivatives". Eur J Med Chem 259. November 2023. doi:10.1016/j.ejmech.2023.115691. PMID 37562117. 
  81. ↑ "Potent and Selective Human 5-HT2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity". J Med Chem 67 (23): 21264–21291. November 2024. doi:10.1021/acs.jmedchem.4c02174. PMID 39589936. 
  82. ↑ "The 5HT2b Receptor in Alzheimer's Disease: Increased Levels in Patient Brains and Antagonist Attenuation of Amyloid and Tau Induced Dysfunction". J Alzheimers Dis 98 (4): 1349–1360. 2024. doi:10.3233/JAD-240063. PMID 38578894. 
  83. ↑ "Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction". Alzheimer's & Dementia: Translational Research & Clinical Interventions 11 (1). 2025. doi:10.1002/trc2.70073. PMID 40151398. 
  84. ↑ "The Novel 5-HT2B Receptor Antagonist, RQ-00310941, Attenuates Visceral Hypersensitivity and Abnormal Defecation in Rat Models". Gastroenterology 140 (5): S–607. 2011. doi:10.1016/S0016-5085(11)62513-4. https://www.gastrojournal.org/article/S0016-5085(11)62513-4/. 
  85. ↑ "RQ 00310941". 17 April 2024. https://adisinsight.springer.com/drugs/800044730. 
  86. ↑ "RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist". British Journal of Pharmacology 127 (5): 1075–82. Jul 1999. doi:10.1038/sj.bjp.0702632. PMID 10455251. 
  87. ↑ "N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea: a novel, high-affinity 5-HT2B receptor antagonist". Journal of Medicinal Chemistry 38 (6): 855–857. March 1995. doi:10.1021/jm00006a001. PMID 7699699. 
  88. ↑ "Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist". British Journal of Pharmacology 126 (3): 572–4. Feb 1999. doi:10.1038/sj.bjp.0702350. PMID 10188965. 
  89. ↑ 89.0 89.1 89.2 "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem 66 (16): 11027–11039. August 2023. doi:10.1021/acs.jmedchem.3c01178. PMID 37584406. 
  90. ↑ 90.0 90.1 "Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension". JACC Basic Transl Sci 8 (10): 1379–1388. October 2023. doi:10.1016/j.jacbts.2023.06.014. PMID 38094686. 
  91. ↑ "A non-hallucinogenic LSD analog with therapeutic potential for mood disorders". Cell Rep 42 (3). March 2023. doi:10.1016/j.celrep.2023.112203. PMID 36884348. 
  92. ↑ "A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses". J Pharmacol Exp Ther 349 (2): 310–318. May 2014. doi:10.1124/jpet.113.212373. PMID 24563531. 
  93. ↑ "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. Sep 2003. doi:10.1124/jpet.103.051797. PMID 12750432. 
  94. ↑ "Delving into the Latest Updates on AMAP-102 with Synapse". 21 November 2024. https://synapse.patsnap.com/drug/5a6e89f25d8d4016838c52e05dc502a2. 
  95. ↑ "Novel 5-HT2A/2C mixed and partial agonist and its efficacy in preclinical pain models". Society for Neuroscience 2024 Annual Meeting, Chicago, October 5–9. October 2024. https://brightmindsbio.com/wp-content/uploads/2024/10/BMB-201-poster-PSPP-final.pdf. 
  96. ↑ "Cariprazine: A Review in Schizophrenia". CNS Drugs 31 (6): 513–525. June 2017. doi:10.1007/s40263-017-0442-z. PMID 28560619. 
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  98. ↑ "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P358. Discovery and Characterization of ITI-1549, a Novel Non-Hallucinogenic Psychedelic for the Treatment of Neuropsychiatric Disorders". Neuropsychopharmacology 48 (Suppl 1): 211–354 (272–273). December 2023. doi:10.1038/s41386-023-01756-4. PMID 38040810. 
  99. ↑ "Küleon Bioscience Announces Scientific Breakthrough with First Known Trifunctional 5-HT2C Receptor Agonist that is also a Full Antagonist of the 5-HT2A and 5-HT2B Receptors, Creating an Exciting Lead for Multiple Neuropsychiatric Illnesses". 5 October 2023. https://www.biospace.com/kueleon-bioscience-announces-scientific-breakthrough-with-first-known-trifunctional-5-ht2c-receptor-agonist-that-is-also-a-full-antagonist-of-the-5-ht2a-and-5-ht2b-receptors-creating-an-exciting-lead-for-multiple-neuropsychiatric-illnesses. 
  100. ↑ "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. 2006. doi:10.1097/00002826-200603000-00005. PMID 16614540. 
  101. ↑ "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology 136 (4): 409–14. Apr 1998. doi:10.1007/s002130050585. PMID 9600588. 
  102. ↑ "Metadoxine extended release (MDX) for adult ADHD". Alcobra Ltd. 2014. http://www.alcobra-pharma.com/products.cfm?productID=142236. 
  103. ↑ "A proposed anti-maladaptive aggression agent classification: improving our approach to treating impulsive aggression". Postgrad Med 131 (2): 129–137. March 2019. doi:10.1080/00325481.2019.1574401. PMID 30678534. 
  104. ↑ "In vitro pharmacological characterization of SPN-810M (molindone)". J Exp Pharmacol 10: 65–73. 2018. doi:10.2147/JEP.S180777. PMID 30538587. 
  105. ↑ "promethazine | Activity data visualisation tool | IUPHAR/BPS Guide to PHARMACOLOGY". http://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7282. 
  106. ↑ "In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties". Br J Pharmacol 117 (3): 427–434. February 1996. doi:10.1111/j.1476-5381.1996.tb15208.x. PMID 8821530. 
  107. ↑ "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. Mar 2009. doi:10.1124/jpet.108.146514. PMID 19050173. 
  108. ↑ "The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo". British Journal of Pharmacology 143 (5): 549–560. Nov 2004. doi:10.1038/sj.bjp.0705929. PMID 15466450. 
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  113. ↑ "Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors". Br J Pharmacol 125 (7): 1413–1420. December 1998. doi:10.1038/sj.bjp.0702201. PMID 9884068. 
  114. ↑ "Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes". J Psychopharmacol 30 (9): 896–912. September 2016. doi:10.1177/0269881116658989. PMID 27464743. 
  115. ↑ "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P361. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Neuropsychopharmacology 48 (Suppl 1): 211–354 (274–275). December 2023. doi:10.1038/s41386-023-01756-4. PMID 38040810. 
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  119. ↑ "Potent and Selective Human 5-HT2B Serotonin Receptor Antagonists: 4'-Cyano-(N)-methanocarba-adenosines by Synthetic Serendipity". J Med Chem 67 (23): 21264–21291. 2024. doi:10.1021/acs.jmedchem.4c02174. PMID 39589936. 
  120. ↑ "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. May 2003. doi:10.1016/s0024-3205(03)00227-3. PMID 12738034. 
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  122. ↑ 122.0 122.1 "Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen". Assay Drug Dev Technol 21 (3): 89–96. April 2023. doi:10.1089/adt.2022.116. PMID 36930852. 
  123. ↑ "Synthesis and Biological Evaluation of Peripheral 5HT2B Antagonists for Liver Fibrosis". J Med Chem 68 (6): 6493–6506. March 2025. doi:10.1021/acs.jmedchem.4c03003. PMID 40048549. 
  124. ↑ "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. January 1993. doi:10.1016/0014-2999(93)90686-c. PMID 8095238. 
  125. ↑ "Serotonin Receptors, 5-th Ligands and Receptor Modeling". Pharmacochemistry Library. 18. Elsevier. 1992. pp. 185–207. doi:10.1016/b978-0-444-88931-7.50017-7. ISBN 978-0-444-88931-7. "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." 
  126. ↑ "Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit". Pharmacol Biochem Behav 77 (3): 623–629. March 2004. doi:10.1016/j.pbb.2003.12.017. PMID 15006475. "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.". 
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Further reading

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