5-HT2B receptor explained

5-Hydroxytryptamine receptor 2B (5-HT_2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene.^{[1] [2]} 5-HT_2B 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-HT_2B receptor is G_q/G₁₁-protein coupled, leading to downstream activation of phospholipase C.

Tissue distribution and function

First discovered in the stomach of rats, 5-HT_2B was challenging to characterize initially because of its structural similarity to the other 5-HT₂ receptors, particularly 5-HT_2C.^[3] The 5-HT₂ receptors (of which the 5-HT_2B 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-HT_2B 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-HT_2B receptor subtype is involved in:

• CNS: inhibition of serotonin and dopamine uptake, behavioral effects^[6]
• Vascular: pulmonary vasoconstriction^[7]
• Cardiac: The 5-HT_2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT_2B 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-HT_2B receptors were discovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.^{[12] [13] [14]}
• Serotonin transporter: 5-HT_2B 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-HT_2B 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-HT_2B 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-HT_2B stimulation.^[20] Today, 5-HT_2B agonism is considered a toxicity signal precluding further clinical development of a compound.^[21]

Ligands

The structure of the 5-HT_2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.^[22] As of 2009, few highly selective 5-HT_2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT_2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT_2B agonists, and the lack of clear therapeutic application for 5-HT_2B antagonists, but there is still a need for selective ligands for scientific research.^[23]

Agonists

Endogenous

• 5-Methoxytryptamine (5-MT) – trace amine^{[24] [25]}
• DMT – trace amine^{[26] [27]}
• Serotonin – neurotransmitter, K_D ≈ 10nM
• Tryptamine – trace amine^{[28] [29]}

Selective

• 6-APB – ~100-fold selectivity over the 5-HT_2A and 5-HT_2C receptors, ≥32-fold selectivity over monoamine release, ~12-fold selectivity over α_2C-adrenergic receptor^[30]
• α-Methylserotonin – ~10-fold selectivity over 5-HT_2A and 5-HT_2C
• BW-723C86 – 100-fold selectivity over 5-HT_2A but only 3- to 10-fold selectivity over 5-HT_2C,^[31] fair functional subtype selectivity, almost full agonist, anxiolytic in vivo^[32]
• LY-266,097 – biased partial agonist in favor of G_q protein, no β-arrestin2 recruitment^[33]
• VU6067416 – modest selectivity over 5-HT_2A and 5-HT_2C^[34]

Non-selective

• 25C-NBOMe
• 25I-NBOMe
• 2C-B^[35]
• 2C-B-FLY
• 2C-C
• 2C-D
• 2C-E
• 2C-I
• 4-Methylamphetamine
• 5-APB
• 5-APDB
• 5-Carboxamidotryptamine
• 5-MAPB^[36]
• 6-APB
• 6-APDB
• 6-MAPB
• 5-MeO-αMT
• 5-MeO-DiPT
• 5-MeO-DMT
• 5-MeO-MiPT
• AL-38022A^[37]
• Aminorex (weakly)^{[38] [39]}
• Ariadne^[40]
• Benfluorex^[41]
• Bromo-dragonfly^{[42] [43] [44]}
• Bromocriptine^[45]
• Cabergoline^[46]
• Chlorphentermine (very weakly)
• CYB210010 (2C-T-TFM)^{[47] [48]}
• Dexfenfluramine
• Dexnorfenfluramine
• Dihydroergocryptine^[49]
• Dihydroergotamine^[50]
• DiPT
• DOB
• DOC
• DOET
• DOI^[51]
• DOM^[52]
• Ergometrine (ergonovine)
• Ergotamine
• Fenfluramine^[53]
• Fenoldopam
• Guanfacine – an α_2A-adrenergic agonist, but has 5-HT_2B agonistic activity at therapeutic concentrations^[54]
• Levofenfluramine
• Levonorfenfluramine
• Lorcaserin
• LSD – about equal affinity for human cloned 5-HT_2B and 5-HT_2A receptors^[55]
• LSM-775^[56]
• mCPP (in humans; weak partial agonist)
• MDA
• MDMA^[57]
• MEM^[58]
• Mescaline^[59]
• Methylergometrine (methylergonovine)
• Methysergide (antagonist in some studies)
• Naphthylaminopropane^[60]
• Norfenfluramine^[31]
• ORG-12962
• ORG-37684
• Oxymetazoline
• Pergolide^[61]
• PNU-22394
• Psilocin^[62]
• Psilocybin
• Quipazine (weak partial agonist)
• Ro60-0175 – functionally selective over 5-HT_2A, potent agonist at both 5-HT_2B/C^[31]
• Ropinirole
• Quinidine
• TFMPP (weak partial agonist)
• VER-3323 – mixed 5-HT_2C and 5-HT_2B agonist with weaker 5-HT_2A affinity
• Xylometazoline

Peripherally selective

• AL-34662 – non-selective over 5-HT_2A and 5-HT_2C^[63]

Inactive

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT_2B receptor agonists, at least in vitro.^[64] These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others.^{[65] [66] [67] [68]} Findings are somewhat conflicting for certain psychedelics, such as psilocin and LSD, but most studies find that these drugs are indeed potent serotonin 5-HT_2B receptor agonists.^[69]

Antagonists

Selective

• 5-HCPC^[70]
• 5-HPEC (weak)
• 5-HPPC
• AM1125
• AM1476
• BF-1 – derived from pimethixene^[71]
• EGIS-7625 – high selectivity over 5-HT_2A^{[72] [73] [74]}
• EXT5 – highly selective^[75]
• EXT9 – somewhat selective
• LY-23,728^[76]
• LY-266,097 – pK_i = 9.7, 100-fold selectivity over 5-HT_2A and 5-HT_2C
• LY-272,015 – fairly selective and highly potent
• LY-287,375^[77]
• MRS7925 – substantially selective over 5-HT_2A and 5-HT_2C but minimal selectivity over the adenosine A₁ receptor^[78]
• MRS8209^[79]
• MW071 (MW01-8-071HAB) – non-MAOI minaprine analogue^[80]
• PRX-08066 – K_i ≈ 1.7nM, >100-fold selectivity
• RQ-00310941 (RQ-941) – K_i = 2.0nM, IC₅₀ = 17nM, >2,000-fold selectivity against >60 targets, under development for medical use^{[81] [82]}
• RS-127,445 (MT-500) – K_i = 0.3nM, >1,000-fold selectivity over 5-HT_2A and 5-HT_2C and numerous other targets, selective over at least eight other serotonin receptors, developed for clinical use but discontinued^{[83] [84]}
• SB-204,741 – >135-fold selectivity over 5-HT_2C and 5-HT_2A^[85]
• SB-215,505 – mixed 5-HT_2B and 5-HT_2C antagonist^[86]
• VU6047534 – weak partial agonist or antagonist, peripherally selective in mice but not humans^[87]

Non-selective

• 2-Bromo-LSD (BOL-148; bromolysergide)^[88]
• (–)-MBP – 5-HT_2A antagonist, 5-HT_2B inverse agonist, and 5-HT_2C agonist^[89]
• AAZ-A-154 (DLX-001)^[90]
• Agomelatine – primarily a melatonin MT₁/MT₂ receptor agonist, with a less potent antagonism of 5-HT_2B and 5-HT_2C^[91]
• AMAP102 (AMAP-102) – 5-HT_2B and 5-HT_2C antagonist^[92]
• Amesergide (LY-237733)
• Amisulpride
• Amitriptyline
• Apomorphine
• Aripiprazole
• Asenapine
• BMB-201 – and active form BMB-39a^[93]
• Brexpiprazole
• Brilaroxazine
• C-122
• Cariprazine^[94]
• Chlorpromazine
• Clozapine
• Cyproheptadine
• Desmethylclozapine (NDMC; norclozapine)
• Ibogainalog^[95]
• ITI-1549^[96]
• KB-128 – 5-HT_2A and 5-HT_2B antagonist and 5-HT_2C agonist^[97]
• Lisuride – a dopamine agonist of the ergoline class, that is also a 5-HT_2B antagonist^[98] and a dual 5-HT_2A/C agonist^[99]
• Lurasidone
• LY-53857
• Mesulergine^[100]
• Metadoxine – a 5-HT_2B antagonist and GABA-activity modulator^[101]
• Metergoline
• Metitepine (methiothepin)
• Mianserin
• Molindone^{[102] [103]}
• N-Methylamisulpride
• Nantenine
• Naphthylpiperazine (1-NP)
• Olanzapine
• Pimethixene
• Pipamperone
• Pizotifen (pizotyline)
• Promethazine^[104]
• Quetiapine
• Rauwolscine
• Risperidone
• Ritanserin
• SB-200,646 – 5-HT_2B/5-HT_2C antagonist, selective over 5-HT_2A
• SB-206,553 – mixed 5-HT_2B and 5-HT_2C antagonist and PAM at α₇ nAChR^{[105] [106]}
• SB-221,284 – 5-HT_2B/5-HT_2C antagonist^[107]
• SB-228,357 – 5-HT_2B/5-HT_2C antagonist
• SDZ SER-082 – a mixed 5-HT_2B/C antagonist
• Spiperone
• Tabernanthalog (TBG; DLX-007)
• Tegaserod – primarily a 5-HT₄ agonist, but also a 5-HT_2B antagonist^{[108] [109]}
• Terguride – an oral, potent antagonist of 5-HT_2A and 5-HT_2B receptors
• Trazodone
• Vabicaserin^[110]
• Viloxazine – weak 5-HT_2B antagonist and 5-HT_2C agonist^{[111] [112]}
• Xanomeline – similar affinity as for muscarinic acetylcholine receptors^{[113] [114] [115]}
• Yohimbine
• Ziprasidone

Unknown or unsorted selectivity

• AM1030 (AM-1030)^[116]

Peripherally selective

• Sarpogrelate (MCI-9042, LS-187,118) – non-selective 5-HT₂ antagonist, but ~2 orders of magnitude lower affinity at 5-HT_2B than at 5-HT_2A^{[117] [118]}
• VU0530244 – 5-HT_2B-selective^[119]
• VU0631019 – 5-HT_2B-selective
• VU6055320 – 5-HT_2B-selective

BW-501C67 and xylamidine are known peripherally selective antagonists of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A and 5-HT_2B receptors, but their serotonin 5-HT_2B receptor interactions do not appear to have been described.^{[120] [121] [122]}

Possible applications

5-HT_2B 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.^[123] More recent research has focused on possible application of 5-HT_2B antagonists as treatments for chronic heart disease.^{[124] [125]} Research claims serotonin 5-HT_2B receptors have effect on liver regeneration.^[126] Antagonism of 5-HT_2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.

See also

• 5-HT receptor

Further reading

• Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN . Multiplicity of mechanisms of serotonin receptor signal transduction . Pharmacology & Therapeutics . 92 . 2–3 . 179–212 . 2002 . 11916537 . 10.1016/S0163-7258(01)00169-3 .
• Choi DS, Birraux G, Launay JM, Maroteaux L . The human serotonin 5-HT2B receptor: pharmacological link between 5-HT2 and 5-HT1D receptors . FEBS Letters . 352 . 3 . 393–9 . Oct 1994 . 7926008 . 10.1016/0014-5793(94)00968-6 . 26931598 . 1994FEBSL.352..393C .
• Kursar JD, Nelson DL, Wainscott DB, Baez M . Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor . Molecular Pharmacology . 46 . 2 . 227–34 . Aug 1994 . 8078486 .
• Schmuck K, Ullmer C, Engels P, Lübbert H . Cloning and functional characterization of the human 5-HT2B serotonin receptor . FEBS Letters . 342 . 1 . 85–90 . Mar 1994 . 8143856 . 10.1016/0014-5793(94)80590-3 . 11232259 . free . 1994FEBSL.342...85S .
• Launay JM, Birraux G, Bondoux D, Callebert J, Choi DS, Loric S, Maroteaux L . Ras involvement in signal transduction by the serotonin 5-HT2B receptor . The Journal of Biological Chemistry . 271 . 6 . 3141–7 . Feb 1996 . 8621713 . 10.1074/jbc.271.6.3141 . free .
• Le Coniat M, Choi DS, Maroteaux L, Launay JM, Berger R . The 5-HT2B receptor gene maps to 2q36.3-2q37.1 . Genomics . 32 . 1 . 172–3 . Feb 1996 . 8786115 . 10.1006/geno.1996.0101 .
• Kim SJ, Veenstra-VanderWeele J, Hanna GL, Gonen D, Leventhal BL, Cook EH . Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder . Molecular and Cellular Probes . 14 . 1 . 47–52 . Feb 2000 . 10722792 . 10.1006/mcpr.1999.0281 .
• Manivet P, Mouillet-Richard S, Callebert J, Nebigil CG, Maroteaux L, Hosoda S, Kellermann O, Launay JM . PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor . The Journal of Biological Chemistry . 275 . 13 . 9324–31 . Mar 2000 . 10734074 . 10.1074/jbc.275.13.9324 . free .
• Becamel C, Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, Lubbert H, Ullmer C . Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1 . The Journal of Biological Chemistry . 276 . 16 . 12974–82 . Apr 2001 . 11150294 . 10.1074/jbc.M008089200 . free .
• Manivet P, Schneider B, Smith JC, Choi DS, Maroteaux L, Kellermann O, Launay JM . The serotonin binding site of human and murine 5-HT2B receptors: molecular modeling and site-directed mutagenesis . The Journal of Biological Chemistry . 277 . 19 . 17170–8 . May 2002 . 11859080 . 10.1074/jbc.M200195200 . free .
• Borman RA, Tilford NS, Harmer DW, Day N, Ellis ES, Sheldrick RL, Carey J, Coleman RA, Baxter GS . 5-HT(2B) receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro . British Journal of Pharmacology . 135 . 5 . 1144–51 . Mar 2002 . 11877320 . 1573235 . 10.1038/sj.bjp.0704571 .
• Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S . Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways . Oncogene . 22 . 21 . 3307–18 . May 2003 . 12761501 . 10.1038/sj.onc.1206406 . 38880905 .
• Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J . Functional activity of serotoninergic and melatoninergic systems expressed in the skin . Journal of Cellular Physiology . 196 . 1 . 144–53 . Jul 2003 . 12767050 . 10.1002/jcp.10287 . 24534729 . free .
• Lin Z, Walther D, Yu XY, Drgon T, Uhl GR . The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse . Pharmacogenetics . 14 . 12 . 805–11 . Dec 2004 . 15608559 . 10.1097/00008571-200412000-00003 .

External links

• Web site: 5-HT_2B . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-11-25 . 2017-02-02 . https://web.archive.org/web/20170202015809/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2322 . dead .

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