5-HT2B receptor

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. 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. 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-HT2B receptor subtype is involved in:

• CNS: inhibition of serotonin and dopamine uptake, behavioral effects
• Vascular: pulmonary vasoconstriction
• Cardiac: The 5-HT2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT2B 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-HT2B receptors were discovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.
• 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, and with the abnormal acute serotonin release produced by drugs such as MDMA. Surprisingly, however, 5-HT2B 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-HT2B 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-HT2B stimulation. Today, 5-HT2B 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-HT2B 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-HT2B receptor antagonism.

Ligands

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

Agonists

Endogenous

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

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

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 α2A-adrenergic agonist, but has 5-HT2B agonistic activity at therapeutic concentrations
• Levofenfluramine
• Levonorfenfluramine
• Lorcaserin
• LSD – about equal affinity for human cloned 5-HT2B and 5-HT2A 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-HT2A, potent agonist at both 5-HT2B/C
• Ropinirole
• Quinidine
• TFMPP (weak partial agonist)
• VER-3323 – mixed 5-HT2C and 5-HT2B agonist with weaker 5-HT2A affinity
• Xylometazoline

Peripherally selective

• AL-34662 – non-selective over 5-HT2A and 5-HT2C

Inactive

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT2B 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-HT2B receptor agonists.

Antagonists

Selective

• 5-HCPC
• 5-HPEC (weak)
• 5-HPPC
• AM1125
• AM1476
• BF-1 – derived from pimethixene
• EGIS-7625 – high selectivity over 5-HT2A
• EXT5 – highly selective
• EXT9 – somewhat selective
• LY-23,728
• LY-266,097 – pKi = 9.7, 100-fold selectivity over 5-HT2A and 5-HT2C
• LY-272,015 – fairly selective and highly potent
• LY-287,375
• MRS7925 – substantially selective over 5-HT2A and 5-HT2C but minimal selectivity over the adenosine A1 receptor
• MRS8209
• MW071 (MW01-8-071HAB) – non-MAOI minaprine analogue
• MW073 – highly selective, orally bioavailable
• PRX-08066 – Ki ≈ 1.7nM, 100-fold selectivity
• RQ-00310941 (RQ-941) – Ki = 2.0nM, IC50 = 17nM, 2,000-fold selectivity against 60 targets, under development for medical use
• 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
• SB-204,741 – 135-fold selectivity over 5-HT2C and 5-HT2A
• SB-215,505 – mixed 5-HT2B and 5-HT2C antagonist
• VU6047534 – weak partial agonist or antagonist, peripherally selective in mice but not humans

Non-selective

• 2-Bromo-LSD (BOL-148; bromolysergide)
• (–)-MBP – 5-HT2A antagonist, 5-HT2B inverse agonist, and 5-HT2C agonist
• Agomelatine – primarily a melatonin MT1/MT2 receptor agonist, with a less potent antagonism of 5-HT2B and 5-HT2C
• AMAP102 (AMAP-102) – 5-HT2B and 5-HT2C antagonist
• Amesergide (LY-237733)
• Amisulpride
• Amitriptyline
• Apomorphine
• Aripiprazole
• Asenapine
• BMB-201 – and active form BMB-39a
• Brexpiprazole
• Brilaroxazine
• C-122
• Cariprazine
• Chlorpromazine
• Clozapine
• Cyproheptadine
• Desmethylclozapine (NDMC; norclozapine)
• Ibogainalog
• ITI-1549
• KB-128 – 5-HT2A and 5-HT2B antagonist and 5-HT2C agonist
• Lisuride – a dopamine agonist of the ergoline class, that is also a 5-HT2B antagonist and a dual 5-HT2A/C agonist
• Lurasidone
• LY-53857
• Mesulergine
• Metadoxine – a 5-HT2B 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-HT2B/5-HT2C antagonist, selective over 5-HT2A
• SB-206,553 – mixed 5-HT2B and 5-HT2C antagonist and PAM at α7 nAChR
• SB-221,284 – 5-HT2B/5-HT2C antagonist
• SB-228,357 – 5-HT2B/5-HT2C antagonist
• SDZ SER-082 – a mixed 5-HT2B/C antagonist
• Spiperone
• Tabernanthalog (TBG; DLX-007)
• Tegaserod – primarily a 5-HT4 agonist, but also a 5-HT2B antagonist
• Terguride – an oral, potent antagonist of 5-HT2A and 5-HT2B receptors
• Trazodone
• Vabicaserin
• Viloxazine – weak 5-HT2B antagonist and 5-HT2C 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-HT2B than at 5-HT2A
• VU0530244 – 5-HT2B-selective
• VU0631019 – 5-HT2B-selective
• VU6055320 – 5-HT2B-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-HT2A and 5-HT2B receptors, but their serotonin 5-HT2B receptor interactions do not appear to have been described.

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

References

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