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

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]

Ligands

The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[22] 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.[23]

Agonists

Selective
  • BW-723C86[24] – fair functional subtype selectivity; almost full agonist. Anxiolytic in vivo[25]
  • Ro60-0175[24] – functionally selective over 5-HT2A, potent agonist at both 5-HT2B/C
  • VER-3323 – selective for 5-HT2B/C over 5-HT2A
  • α-Methyl-5-HT – moderately selective over 5-HT2A/C
  • 6-APB
  • LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[26]
Non-selective

Antagonists

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.[43] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[44][45] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[46] 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/sites/entrez?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. 
  3. ↑ Frazer, Alan; Hensler, Julie G. (1999). "Serotonin" (in en). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincott-Raven. 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. S. J. Enna, David B. Bylund, Elsevier Science. Amsterdam: Elsevier. 2008. ISBN 978-0-08-055232-3. OCLC 712018683. https://www.worldcat.org/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. 
  10. ↑ Padhariya, Komal; Bhandare, Richie; Canney, Daniel; Velingkar, Vinay (2017-12-12). "Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists" (in en). Cardiovascular & Hematological Disorders Drug Targets 17 (2): 86–104. doi:10.2174/1871529X17666170703115111. PMID 28676029. http://www.eurekaselect.com/153656/article. 
  11. ↑ Neugebauer, Volker (2020), "Serotonin—pain modulation", Handbook of the Behavioral Neurobiology of Serotonin, Handbook of Behavioral Neuroscience, 31, Elsevier, pp. 309–320, doi:10.1016/b978-0-444-64125-0.00017-7, ISBN 9780444641250, http://dx.doi.org/10.1016/b978-0-444-64125-0.00017-7, retrieved 2022-07-04 
  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. 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. ↑ Cavero, Icilio; Guillon, Jean-Michel (2014-03-01). "Safety Pharmacology assessment of drugs with biased 5-HT2B receptor agonism mediating cardiac valvulopathy" (in en). Journal of Pharmacological and Toxicological Methods 69 (2): 150–161. doi:10.1016/j.vascn.2013.12.004. ISSN 1056-8719. PMID 24361689. https://www.sciencedirect.com/science/article/pii/S1056871913003262. 
  22. ↑ 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. 
  23. ↑ 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.
  24. ↑ 24.0 24.1 24.2 "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. 
  25. ↑ "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. 
  26. ↑ "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. 
  27. ↑ "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. 
  28. ↑ 28.0 28.1 "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. 
  29. ↑ Manzoni, Olivier Jacques, ed (2010). "Psychedelics and the human receptorome". PLOS ONE 5 (2): e9019. doi:10.1371/journal.pone.0009019. PMID 20126400. Bibcode: 2010PLoSO...5.9019R. 
  30. ↑ "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. 
  31. ↑ 31.0 31.1 "PDSP Ki database, University of North Carolina at Chapel Hill". https://pdsp.unc.edu/databases/kidb.php. 
  32. ↑ "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. 
  33. ↑ Garnock-Jones, Karly P. (June 2017). "Cariprazine: A Review in Schizophrenia". CNS Drugs 31 (6): 513–525. doi:10.1007/s40263-017-0442-z. ISSN 1179-1934. PMID 28560619. 
  34. ↑ "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. 
  35. ↑ "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. 
  36. ↑ "The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo". British Journal of Pharmacology 143 (5): 549–60. Nov 2004. doi:10.1038/sj.bjp.0705929. PMID 15466450. 
  37. ↑ "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. 
  38. ↑ "Metadoxine extended release (MDX) for adult ADHD". Alcobra Ltd. 2014. http://www.alcobra-pharma.com/products.cfm?productID=142236. 
  39. ↑ "promethazine | Activity data visualisation tool | IUPHAR/BPS Guide to PHARMACOLOGY". http://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7282. 
  40. ↑ "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. 
  41. ↑ "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. Mar 2009. doi:10.1124/jpet.108.146514. PMID 19050173. 
  42. ↑ "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. 
  43. ↑ "The emergence of selective 5-HT 2B antagonists structures, activities and potential therapeutic applications". Mini Reviews in Medicinal Chemistry 4 (3): 325–30. Mar 2004. doi:10.2174/1389557043487312. PMID 15032678. 
  44. ↑ "Serotonin 5-HT2B receptor in cardiac fibroblast contributes to cardiac hypertrophy: a new therapeutic target for heart failure?". Circulation Research 104 (1): 1–3. Jan 2009. doi:10.1161/CIRCRESAHA.108.191122. PMID 19118279. 
  45. ↑ "A new class of 5-HT2B antagonists possesses favorable potency, selectivity, and rat pharmacokinetic properties". Bioorganic & Medicinal Chemistry Letters 19 (8): 2206–10. Apr 2009. doi:10.1016/j.bmcl.2009.02.126. PMID 19307114. 
  46. ↑ "Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease". Nature Medicine 17 (12): 1668–73. Dec 2011. doi:10.1038/nm.2490. PMID 22120177. 

Further reading

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