5-HT2B receptor

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. 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. 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. However, its most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.

The 5-HT_2B receptor subtype is involved in:

• CNS: inhibition of serotonin and dopamine uptake, behavioral effects
• Vascular: pulmonary vasoconstriction
• 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. Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts, with chronic overstimulation leading to valvulopathy. 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.
• 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, and with the abnormal acute serotonin release produced by drugs such as MDMA. Surprisingly, however, 5-HT_2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels, despite its role in modulating serotonin release.

Clinical significance

Valvular heart disease

5-HT_2B receptors have been strongly implicated in causing drug-induced valvular heart disease. The Fen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT_2B stimulation. Today, 5-HT_2B agonism is considered a toxicity signal precluding further clinical development of a compound.

Migraines

The non-selective serotonin receptor agonist meta-chlorophenylpiperazine (mCPP) induces migraines and this may be due to serotonin 5-HT_2B receptor agonism. 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-HT_2B receptor antagonism.

Ligands

The structure of the 5-HT_2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine. 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.

Agonists

Endogenous

• 5-Methoxytryptamine (5-MT) – trace amine
• DMT – trace amine
• Serotonin – neurotransmitter, K_D ≈ 10nM
• Tryptamine – trace amine

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
• 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, fair functional subtype selectivity, almost full agonist, anxiolytic in vivo
• LY-266,097 – biased partial agonist in favor of G_q protein, no β-arrestin2 recruitment
• VU6067416 – modest selectivity over 5-HT_2A and 5-HT_2C

Non-selective

• 25C-NBOMe
• 25I-NBOMe
• 2C-B
• 2C-B-FLY
• 2C-C
• 2C-D
• 2C-E
• 2C-I
• 4-Methylamphetamine
• 5-APB
• 5-APDB
• 5-Carboxamidotryptamine
• 5-MAPB
• 6-APB
• 6-APDB
• 6-MAPB
• 5-MeO-αMT
• 5-MeO-DiPT
• 5-MeO-DMT
• 5-MeO-MiPT
• AL-38022A
• Aminorex (weakly)
• Ariadne
• Benfluorex
• Bromo-dragonfly
• Bromocriptine
• Cabergoline
• Chlorphentermine (very weakly)
• CYB210010 (2C-T-TFM)
• Dexfenfluramine
• Dexnorfenfluramine
• Dihydroergocryptine
• Dihydroergotamine
• DiPT
• DOB
• DOC
• DOET
• DOI
• DOM
• Ergometrine (ergonovine)
• Ergotamine
• Fenfluramine
• Fenoldopam
• Guanfacine – an α_2A-adrenergic agonist, but has 5-HT_2B agonistic activity at therapeutic concentrations
• Levofenfluramine
• Levonorfenfluramine
• Lorcaserin
• LSD – about equal affinity for human cloned 5-HT_2B and 5-HT_2A receptors
• LSM-775
• mCPP (in humans; weak partial agonist)
• MDA
• MDMA
• MEM
• Mescaline
• Methylergometrine (methylergonovine)
• Methysergide (antagonist in some studies)
• Naphthylaminopropane
• Norfenfluramine
• ORG-12962
• ORG-37684
• Oxymetazoline
• Pergolide
• PNU-22394
• Psilocin
• Psilocybin
• Quipazine (weak partial agonist)
• Ro60-0175 – functionally selective over 5-HT_2A, potent agonist at both 5-HT_2B/C
• 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

Inactive

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT_2B receptor agonists, at least in vitro. These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others. 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.

Antagonists

Selective

• 5-HCPC
• 5-HPEC (weak)
• 5-HPPC
• AM1125
• AM1476
• BF-1 – derived from pimethixene
• EGIS-7625 – high selectivity over 5-HT_2A
• EXT5 – highly selective
• EXT9 – somewhat selective
• LY-23,728
• 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
• MRS7925 – substantially selective over 5-HT_2A and 5-HT_2C but minimal selectivity over the adenosine A₁ receptor
• MRS8209
• MW071 (MW01-8-071HAB) – non-MAOI minaprine analogue
• MW073 – highly selective, orally bioavailable
• 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
• 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
• SB-204,741 – >135-fold selectivity over 5-HT_2C and 5-HT_2A
• SB-215,505 – mixed 5-HT_2B and 5-HT_2C antagonist
• VU6047534 – weak partial agonist or antagonist, peripherally selective in mice but not humans

Non-selective

• 2-Bromo-LSD (BOL-148; bromolysergide)
• (–)-MBP – 5-HT_2A antagonist, 5-HT_2B inverse agonist, and 5-HT_2C agonist
• Agomelatine – primarily a melatonin MT₁/MT₂ receptor agonist, with a less potent antagonism of 5-HT_2B and 5-HT_2C
• AMAP102 (AMAP-102) – 5-HT_2B and 5-HT_2C antagonist
• Amesergide (LY-237733)
• Amisulpride
• Amitriptyline
• Apomorphine
• Aripiprazole
• Asenapine
• BMB-201 – and active form BMB-A39a
• Brexpiprazole
• Brilaroxazine
• C-122
• Cariprazine
• Chlorpromazine
• Clozapine
• Cyproheptadine
• Desmethylclozapine (NDMC; norclozapine)
• Ibogainalog
• ITI-1549
• KB-128 – 5-HT_2A and 5-HT_2B antagonist and 5-HT_2C agonist
• Lisuride – a dopamine agonist of the ergoline class, that is also a 5-HT_2B antagonist and a dual 5-HT_2A/C agonist
• Lurasidone
• LY-53857
• Mesulergine
• Metadoxine – a 5-HT_2B antagonist and GABA-activity modulator
• Metergoline
• Metitepine (methiothepin)
• Mianserin
• Molindone
• N-Methylamisulpride
• Nantenine
• Naphthylpiperazine (1-NP)
• Olanzapine
• Pimethixene
• Pipamperone
• Pizotifen (pizotyline)
• Promethazine
• 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
• SB-221,284 – 5-HT_2B/5-HT_2C antagonist
• 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
• Terguride – an oral, potent antagonist of 5-HT_2A and 5-HT_2B receptors
• Trazodone
• Vabicaserin
• Viloxazine – weak 5-HT_2B antagonist and 5-HT_2C agonist
• Xanomeline – similar affinity as for muscarinic acetylcholine receptors
• Yohimbine
• Zalsupindole (DLX-001; AAZ-A-154)
• Ziprasidone

Unknown or unsorted selectivity

• AM1030 (AM-1030)
• TN-002

Peripherally selective

• MRS8209
• 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
• VU0530244 – 5-HT_2B-selective
• VU0631019 – 5-HT_2B-selective
• VU6055320 – 5-HT_2B-selective
• Others (e.g., "compound 19c")

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.

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. More recent research has focused on possible application of 5-HT_2B antagonists as treatments for chronic heart disease. Research claims serotonin 5-HT_2B receptors have effect on liver regeneration. 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

References

Further reading

External links