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5-HT2B receptor
5-HT2B receptor
5-HT2B receptor
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HTR2B
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHTR2B, 5-HT(2B), 5-HT2B, 5-HT-2B, 5-hydroxytryptamine receptor 2B
External IDsOMIM: 601122; MGI: 109323; HomoloGene: 55492; GeneCards: HTR2B; OMA:HTR2B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3357

15559

Ensembl

ENSG00000135914

ENSMUSG00000026228

UniProt

P41595

Q02152

RefSeq (mRNA)

NM_000867
NM_001320758

NM_008311

RefSeq (protein)

NP_000858
NP_001307687

NP_032337

Location (UCSC)Chr 2: 231.11 – 231.13 MbChr 1: 86.03 – 86.04 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene.[5][6] 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

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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.[7] 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.[8] However, its most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.[9]

The 5-HT2B receptor subtype is involved in:

  • CNS: inhibition of serotonin and dopamine uptake, behavioral effects[10]
  • Vascular: pulmonary vasoconstriction[11]
  • Cardiac: The 5-HT2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice.[12] Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts,[13] with chronic overstimulation leading to valvulopathy.[14][15] 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.[16][17][18]
  • 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,[19] and with the abnormal acute serotonin release produced by drugs such as MDMA.[10] Surprisingly, however, 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels,[20] despite its role in modulating serotonin release.

Clinical significance

[edit]

Valvular heart disease

[edit]

5-HT2B receptors have been strongly implicated in causing drug-induced valvular heart disease.[21][22][23] The Fen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT2B stimulation.[24] Today, 5-HT2B agonism is considered a toxicity signal precluding further clinical development of a compound.[25]

Migraines

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The non-selective serotonin receptor agonist meta-chlorophenylpiperazine (mCPP) induces migraines and this may be due to serotonin 5-HT2B receptor agonism.[26] 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.[26]

Ligands

[edit]

The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[27] 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.[28]

Agonists

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Endogenous

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Selective

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  • 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[31][38]
  • α-Methylserotonin – ~10-fold selectivity over 5-HT2A and 5-HT2C[35][39][37]
  • BW-723C86 – 100-fold selectivity over 5-HT2A but only 3- to 10-fold selectivity over 5-HT2C,[35][40] fair functional subtype selectivity, almost full agonist, anxiolytic in vivo[41]
  • LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[42]
  • VU6067416 – modest selectivity over 5-HT2A and 5-HT2C[43]

Non-selective

[edit]

Peripherally selective

[edit]

Inactive

[edit]

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT2B receptor agonists, at least in vitro.[31] These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others.[31][48][38][72][73][74] 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.[64][31][33]

Antagonists

[edit]

Selective

[edit]

Non-selective

[edit]

Unknown or unsorted selectivity

[edit]

Peripherally selective

[edit]

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.[128][129][130]

Possible applications

[edit]

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.[131] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[132][133] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[134] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

5-HT2B receptor

View on Grokipedia
from Grokipedia
The 5-HT2B receptor, encoded by the HTR2B gene on human chromosome 2q37.1, is a class A G protein-coupled receptor (GPCR) that selectively binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) with high affinity (pKi 7.9–8.4). It consists of 481 amino acids forming seven transmembrane helices, three extracellular and three intracellular loops, and N- and C-terminal domains, with a molecular weight of approximately 54.3 kDa. As a member of the 5-HT2 receptor subfamily, it plays critical roles in mediating serotonin's effects on cellular proliferation, contraction, and signaling across multiple physiological systems. Upon , the 5-HT2B receptor primarily couples to Gq/11 proteins, triggering C-β (PLC-β) , which hydrolyzes (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). This cascade elevates intracellular calcium levels and activates (PKC), leading to downstream effects such as ERK1/2 and transcription modulation. It also exhibits biased , particularly through β-arrestin pathways, which can influence non-canonical signaling like Src kinase and TGF-β-mediated . Crystal structures, such as those bound to ergotamine (PDB ID: 4IB4 at 2.7 Å resolution), have elucidated orthosteric and extended binding pockets that accommodate diverse ligands. The receptor is widely expressed in human tissues, with highest levels in the , trachea, , liver, heart, and ovaries, as detected by RT-PCR, while in it predominates in the fundus and vascular . Physiologically, it regulates cardiovascular development and , including formation and endothelial relaxation; gastrointestinal motility via contraction; pulmonary function in arterial ; and central nervous system processes like release, perception, and . In immune cells such as and macrophages, it contributes to inflammatory responses. Dysregulation is implicated in pathologies including cardiac valvulopathy, pulmonary arterial , organ (e.g., liver and lung), , and certain cancers like . Pharmacologically, the 5-HT2B receptor is targeted by selective antagonists like RS 127445 (pKi 9.0–9.5) and PRX-08066 (Ki ~3.4 nM), which have shown promise in preclinical models for and , while agonists such as diethylamide (; pKi 9.0) and methylergonovine (pKi 9.3) are associated with adverse effects like , prompting off-target screening in . Genetic studies, including mice exhibiting lethal heart defects, underscore its essential role in embryogenesis and adult tissue maintenance.

Genetics and molecular structure

Gene characteristics

The HTR2B gene, which encodes the 5-HT2B receptor, is located on the long arm of human at the cytogenetic band 2q37.1, spanning genomic positions 231,108,230 to 231,125,042 on the reverse strand in the GRCh38.p14 assembly. The gene comprises 4 exons, with the canonical transcript (ENST00000258400.4) producing an mRNA of 2,170 nucleotides that encodes a 481-amino acid protein precursor. Alternative splicing yields additional transcripts, though the canonical isoform predominates in most tissues. Evolutionary conservation of HTR2B is evident across mammals, with the human protein sharing approximately 82% sequence identity with the ortholog and 79% with the ortholog, reflecting conserved functional domains despite species-specific variations. A notable genetic variant is the Q20* mutation (c.58C>T), which truncates the protein and has been associated with severe and alcohol-related risk behaviors, particularly in Finnish populations where it reaches a minor allele frequency of about 2%. Transcriptional regulation of HTR2B occurs through promoter elements approximately 1.5 kb upstream of the transcription start site, which contain binding sites responsive to transcription factors including Sp1, which activates expression in microglial cells, and nuclear factor I (NFI), which positively regulates transcription in cells.

Protein structure

The 5-HT2B receptor belongs to the rhodopsin-like subfamily (family A) of G protein-coupled receptors (GPCRs), which are characterized by a conserved consisting of seven transmembrane α-helices (TM1–TM7) connected by three extracellular loops (ECL1–ECL3) and three intracellular loops (ICL1–ICL3), with an extracellular and an intracellular . This topology positions the orthosteric ligand-binding site within the transmembrane bundle, accessible from the . The first high-resolution structure of the 5-HT2B receptor was obtained in 2013 via of a thermostabilized chimeric construct bound to the agonist ergotamine, resolved at 2.7 (PDB ID: 4IB4). In this active-like conformation, the orthosteric binding pocket is a narrow cavity formed by residues from TM3, TM5, TM6, and the second extracellular loop (ECL2), with ergotamine's core engaging hydrophobic interactions and its basic amine forming a with the conserved Asp3.32 (Asp129) in TM3. Key structural motifs include the DRY sequence (Asp-Arg-Tyr) at the TM3–ICL2 junction, which stabilizes the inactive state through an ionic lock but rearranges upon activation to facilitate coupling, and the conserved Asp3.32 in TM3, essential for coordinating the positively charged amine of endogenous ligands like serotonin. Recent cryo-electron microscopy (cryo-EM) structures, determined in 2022, have captured the 5-HT2B receptor in complex with in transducer-free (2.7 Å), Gq-coupled (2.9 Å), and β-arrestin-1-coupled (3.3 Å) states (PDB IDs: 7SRQ, 7SRR, 7SRS), revealing conformational shifts that underlie biased signaling, including outward movement of TM6 and rearrangements in ICL2 that accommodate different transducers. These structures highlight ligand-specific pocket expansions and intracellular rearrangements promoting biased agonism towards Gq and β-arrestin pathways. Post-translational modifications of the 5-HT2B receptor include N-linked , with consensus sites in the (e.g., Asn7) and ECL2 that influence receptor trafficking and membrane expression; glycosylation at ECL2 has been resolved in structural studies and contributes to stabilizing extracellular domains.

Tissue distribution

Central nervous system expression

The 5-HT2B receptor is expressed in various regions of the , with notable levels in key brain areas involved in emotion, cognition, and motor control. High mRNA and protein expression has been reported in the frontal cortex and , while moderate expression occurs in the ; lower levels are observed in the . In the hippocampus, expression is moderate, contributing to its potential role in limbic functions. At the cellular level, the 5-HT2B receptor is predominantly localized to neurons, including subpopulations of serotonergic neurons in the dorsal raphe nuclei and neurons in the mesoaccumbens pathway. It is also expressed on , the primary immune cells of the brain, where it influences neuroinflammatory responses. Immunohistochemical studies confirm its distribution on both presynaptic and postsynaptic sites in cortical and striatal neurons, supporting bidirectional modulation of . Quantitative assessments using (RT-PCR) indicate that 5-HT2B mRNA levels are substantially higher in the compared to the , with fold differences ranging from 5- to 10-fold in models under baseline conditions. These patterns highlight region-specific roles in serotonergic signaling. During development, 5-HT2B receptor expression is upregulated in the early embryonic , peaking around embryonic days 8-9 in mice, particularly in neural structures including the that give rise to serotonergic projections. This temporal profile suggests involvement in and circuit formation.

Peripheral tissue expression

The 5-HT2B receptor exhibits prominent expression in several peripheral tissues, particularly within the cardiovascular system, where it is found in valvular interstitial cells of heart valves and the of the . High expression is also observed in the , trachea, , ovaries, and other reproductive and respiratory tissues. Radioligand binding assays quantify receptor density in human cardiac valves at approximately 28.8 fmol/mg protein across aortic, mitral, tricuspid, and pulmonary valves. In the gastrointestinal tract, the receptor is expressed in smooth muscle cells, with notable levels in the colon. Hepatic expression occurs primarily in hepatocytes and hepatic stellate cells, contributing to its role in liver physiology. mRNA distribution studies via RT-PCR and RNA-seq reveal high levels of 5-HT2B expression in human uterus, small intestine, trachea, liver, heart, and ovaries, with moderate levels in kidney, lung, pancreas, and spleen; protein confirmation via Western blot supports these patterns in analogous rodent tissues like stomach and heart. Expression is also evident in immune-associated cells, with elevated levels on fibroblasts and myofibroblasts, especially in fibrotic contexts such as and dermal tissues. These cells show receptor presence via immunohistochemical and mRNA analyses in conditions like and systemic sclerosis. Species differences influence peripheral expression profiles: in humans, 5-HT2B mRNA is abundant in , , and trachea among others, whereas in , it predominates in the fundic , affecting the suitability of translational models for peripheral receptor studies. This human-rodent disparity highlights broader peripheral distribution in humans compared to the more restricted rodent pattern.

Function and signaling

Signal transduction mechanisms

The 5-HT2B receptor, a (GPCR), primarily couples to Gq/11 proteins upon activation by serotonin (5-HT), initiating a canonical signaling cascade. This coupling activates C-β (PLC-β), which hydrolyzes (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores, while DAG activates (PKC), amplifying downstream effects such as and cellular proliferation. In addition to Gq/11-mediated pathways, the 5-HT2B receptor engages β-arrestin recruitment, which scaffolds and activates the (MAPK)/extracellular signal-regulated kinase (ERK) pathway, promoting cell proliferation and differentiation independently of signaling. Receptor desensitization occurs through of the C-terminal tail by G protein-coupled receptor kinases (GRKs), particularly GRK2, and PKC, which uncouples the receptor from Gq/11 and facilitates β-arrestin binding. This promotes clathrin-mediated internalization, terminating signaling and enabling receptor or degradation.

Physiological roles

The 5-HT2B receptor contributes to cardiovascular , particularly in the maintenance of integrity. In valvular interstitial cells, activation of this receptor supports cellular responses that preserve tissue structure under hemodynamic stress, ensuring proper valve function without excessive remodeling. Additionally, the receptor modulates pulmonary , where serotonin signaling through 5-HT2B facilitates acute responses to hypoxia in pulmonary artery cells, aiding in the regulation of pulmonary vascular tone during normal physiological conditions. In the , the 5-HT2B receptor mediates excitatory effects on , promoting colonic motility through contraction and coordination of peristaltic activity. This role is evident in colon preparations, where receptor enhances serotonin-induced contractions that support digestive transit. Within the , the 5-HT2B receptor modulates release in the and , influencing reward processing and . It also contributes to , with mediating mechanical through regulation of transient receptor potential 1 in sensory neurons. Genetic variants in the HTR2B gene, such as a polymorphism, are associated with increased , particularly in the context of alcohol consumption, as demonstrated in and studies. Beyond these systems, the 5-HT2B receptor promotes proliferation during , where it enhances and extracellular matrix remodeling to support tissue repair. In injury models, serotonin release activates the receptor on s, driving their expansion without leading to in controlled physiological contexts. In liver regeneration following partial , the receptor modulates proliferation, acting as a regulatory brake on regenerative growth to prevent over-expansion while allowing restoration of liver mass.

Pharmacology

Agonists

The primary endogenous for the 5-HT2B receptor is serotonin (5-HT), which serves as the orthosteric and activates the receptor with an ranging from approximately 4 to 20 nM in functional assays measuring phosphoinositide or calcium . This potency underscores serotonin's central role in mediating 5-HT2B-dependent signaling across various tissues. Among selective synthetic agonists, BW 723C86 stands out as a high-affinity, orally active compound with preferential activity at the 5-HT2B receptor (Ki ≈ 4 nM) and notable use in preclinical studies of peripheral gastrointestinal function. Similarly, , a derivative classified as an , functions as a at the 5-HT2B receptor, displaying nanomolar potency in functional assays while also interacting with other serotonin receptors and monoamine transporters. Non-selective agonists include metabolites of , such as norfenfluramine, which bind with high affinity (Ki 10–50 nM) and act as full agonists at the 5-HT2B receptor in contractile and binding assays. derivatives like also exhibit potent full agonism (pEC50 8.42) at this receptor, contributing to their broader pharmacological profile across and serotonin systems.
CompoundTypeAffinity/PotencyKey NotesSource
Serotonin (5-HT)EndogenousEC50 4–20 nMOrthosteric full Pharmacological evidence for a functional serotonin-2B receptor...
BW 723C86Selective syntheticKi ≈ 4 nMPeripheral GI focusBW 723C86, a 5-HT2B receptor agonist...
Selective synthetic (partial)Nanomolar Pharmacological profile of novel psychoactive benzofurans
NorfenfluramineNon-selective (fenfluramine )Ki 10–50 nMFull Evidence for Possible Involvement of 5-HT2B Receptors...
Non-selective ()pEC50 8.42Full Agonism at 5-HT2B receptors is not a class effect...
In contrast, compounds like DOI demonstrate selectivity within the 5-HT2 family, acting as a potent at the (Ki ≈ 0.5 nM) but showing substantially lower affinity and negligible functional activity at the 5-HT2B receptor (Ki > 100 nM). This distinction highlights the structural basis for subtype-specific agonism.

Antagonists

Antagonists of the 5-HT2B receptor inhibit the binding of serotonin to this , thereby blocking downstream signaling pathways such as activation and calcium mobilization. These compounds are valuable tools for dissecting the receptor's role in physiological processes and have been characterized through radioligand binding assays, often using [3H]- or [3H]-5-HT as tracers to measure displacement and determine inhibition constants (Ki) or half-maximal inhibitory concentrations (). Selectivity is typically assessed against related 5-HT2A and 5-HT2C subtypes, with high-affinity antagonists exhibiting nanomolar potencies and substantial fold-selectivity to minimize off-target effects. Selective 5-HT2B antagonists include RS-127445, a high-affinity compound with a pKi of 9.5 at recombinant 5-HT2B receptors, demonstrating approximately 1000-fold selectivity relative to 5-HT2A and 5-HT2C subtypes in radioligand binding assays using [3H]-LSD displacement in CHO cell membranes. This orally bioavailable agent has been widely used in preclinical studies to probe 5-HT2B-mediated responses without significant interference at other serotonin receptors. Similarly, SB-204741 serves as a potent selective with a pA2 of 7.95 (equivalent to Ki ≈11 nM) at 5-HT2B, showing at least 135-fold selectivity over 5-HT2C and greater than 1000-fold over 5-HT2A, particularly emphasizing its utility in peripheral tissues where 5-HT2B expression is prominent. LY-266,097 represents an early selective with a pKi of 9.3 (Ki ≈ 0.5 nM) for 5-HT2B, displaying over 100-fold selectivity against 5-HT2A and 5-HT2C in binding assays on human embryonic kidney (HEK293) cell membranes expressing the receptor; its tetrahydro-β-carboline structure contributes to a mixed pharmacological profile in functional assays, though it remains a standard tool for 5-HT2B blockade. Non-selective antagonists, such as the ergot derivative , exhibit broader activity across subtypes, with a Ki of approximately 9 nM at 5-HT2B determined via [3H]-LSD binding in human receptor assays, alongside comparable affinities at 5-HT2A (Ki ≈ 3 nM) and 5-HT2C (Ki ≈ 1 nM), making it useful for prophylaxis but less ideal for subtype-specific investigations. Among peripherally selective agents, MARY1, discovered in 2025, is a novel high-affinity 5-HT2B with an of 380 nM and Ki of 764 nM in human 5-HT2B-expressing cells using [3H]-5-HT displacement assays, showing subtype selectivity and preferential activity in renal tissues where it promotes through receptor blockade without notable penetration. The following table summarizes representative binding affinities for these antagonists from key radioligand studies:
Antagonist5-HT2B Ki/IC50 (nM)Selectivity (fold over 5-HT2A/C)Assay TypeSource
RS-127445pKi = 9.5 (Ki ≈0.3)≈1000[3H]-LSD displacementKnight et al., 1997
SB-204741pA2 = 7.95 (Ki ≈11)≥135 over 2C; >1000 over 2A[3H]-5-HT bindingKennett et al., 1995
LY-266,097pKi = 9.3 (Ki ≈0.5)>100[3H]-LSD displacementKnight et al., 2004
MethysergideKi ≈ 9Low (≈1-2)[3H]-LSD binding (human)Fitzgerald et al., 2000
MARY1Ki = 764; IC50=380Subtype-selective (peripheral)[3H]-5-HT displacementVictor et al., 2025

Clinical significance

Cardiovascular effects

The 5-HT2B receptor plays a critical role in the pathogenesis of (VHD), where chronic activation by serotonergic agonists promotes fibrotic plaque formation on cardiac valves. Activation of 5-HT2B receptors on valve interstitial cells triggers mitogenic signaling pathways, including (MAPK) activation, leading to excessive production and valve thickening, which can progress to regurgitation or stenosis. Drugs such as and its metabolite norfenfluramine, as well as , act as potent agonists at these receptors, with norfenfluramine exhibiting high-affinity full agonism (EC50 ≈ 10-50 nmol/L), contributing to the observed VHD in clinical use. This association prompted the U.S. (FDA) to issue warnings for 5-HT2B agonists starting around 2000, following the withdrawal of in 1997 due to a 23-35% incidence of valvular abnormalities in users, and similar actions for by 2003-2007. In pulmonary arterial hypertension (PAH), 5-HT2B receptor antagonism has demonstrated therapeutic potential by mitigating vascular remodeling and reducing pulmonary pressures in preclinical models. Overexpression of 5-HT2B in pulmonary arteries drives proliferation and , exacerbating PAH; selective antagonists like SB204741 prevent these effects in BMPR2 mutant mice, normalizing vessel stiffness (from 90 kPa to 45 kPa) and reducing right ventricular systolic pressure (RVSP) by approximately 50% compared to vehicle-treated controls. Similarly, compounds such as PRX-08066 and VU6047534 (as antagonists or partial agonists) decrease muscularization of small pulmonary arterioles (0-25 μm) and induce modest but significant RVSP drops (20-50%) in monocrotaline- and Sugen-hypoxia-induced PAH models, highlighting antagonism's role in limiting inflammatory cell recruitment and SRC kinase-mediated cytoskeletal changes. Beyond VHD and PAH, 5-HT2B activation in cardiac fibroblasts contributes to risk, particularly through enhanced fibrotic remodeling that disrupts electrical conduction. In post-myocardial infarction models, 5-HT2B signaling in border zone fibroblasts promotes activation and formation, increasing susceptibility to ventricular s; genetic deletion or antagonism of 5-HT2B reduces thickness and prevents inducible s by modulating expression and conduction heterogeneity. Recent 2023 research has explored peripherally restricted 5-HT2B partial agonists, such as VU6047534, which effectively treat PAH in models by lowering RVSP and vascular without inducing cardiac , owing to minimal penetration (Kp = 0.02) and avoidance of valvular agonism.

Neurological and psychiatric implications

The 5-HT2B receptor has been implicated in the of migraines through its activation in meningeal tissues, where it contributes to and vascular headache by sensitizing endings. Studies indicate that 5-HT2B promotes the release of inflammatory mediators from trigeminal ganglia, exacerbating pain signaling during attacks. Ergotamine derivatives, such as , exert antimigraine effects partly via at 5-HT2B receptors, though chronic use carries a risk of (VHD) due to sustained receptor activation leading to fibrotic valve lesions. In depression and mood disorders, the 5-HT2B receptor, particularly on , plays a role in serotonergic signaling. Activation of astrocytic 5-HT2B receptors by selective serotonin reuptake inhibitors (SSRIs) such as exerts effects through β-arrestin2-dependent mechanisms, promoting (BDNF) synthesis and suppressing astrocyte-microglia crosstalk that could contribute to . Elevated 5-HT2B receptor levels have been documented in postmortem brain tissues from patients, particularly in regions affected by amyloid-beta and , suggesting a role in disease progression through exacerbated and impaired . A 2024 study highlights that 5-HT2B antagonists can attenuate amyloid-beta oligomer-induced synaptic deficits and hyperphosphorylation in preclinical models, restoring and cognitive function without affecting baseline neurotransmission. This positions 5-HT2B as a potential modulator of Alzheimer's-related neurodegeneration. The 5-HT2B receptor's cortical expression implicates it in , where altered serotonergic signaling may contribute to psychotic symptoms via interactions with pathways in prefrontal regions. Genetic variants in the HTR2B gene, such as a population-specific , have been associated with increased and aggressive behaviors, underscoring the receptor's influence on executive control and behavioral inhibition in psychiatric contexts.

Other disease associations

Activation of the 5-HT2B receptor in contributes to the progression of (IPF) by promoting deposition and differentiation. Studies have shown increased 5-HT2B receptor expression in fibrotic tissues of IPF patients, with antagonism reducing key fibrotic events such as synthesis and myofibroblast activation in preclinical models. Similarly, in systemic sclerosis (SSc), elevated 5-HT2B receptor signaling drives dermal and pulmonary through enhanced transforming growth factor-β (TGF-β) pathways in fibroblasts. Selective 5-HT2B antagonists, such as AM1476, have demonstrated antifibrotic effects in SSc models by attenuating thickening and . In 2025, the highlighted next-generation 5-HT2B receptor antagonists as promising disease-modifying agents for disorders, including IPF and SSc, due to their nanomolar potency and selectivity in preclinical fibrosis models. Overexpression of the 5-HT2B receptor (HTR2B) in colorectal cancer tissues correlates with tumor proliferation, invasion, and metastasis, positioning it as a potential prognostic marker. Activation of HTR2B by serotonin enhances colorectal tumor growth via downstream signaling that supports epithelial-mesenchymal transition and angiogenesis. High HTR2B expression identifies an aggressive subtype of colorectal cancer with increased proliferative capacity, as observed in patient cohorts and cell line studies. Antagonism of HTR2B has shown potential to inhibit tumor progression in preclinical models, suggesting its role as a therapeutic target beyond its prognostic value. In non-alcoholic (), 5-HT2B receptor activation in hepatic stellate cells exacerbates liver by promoting their into myofibroblasts and production. Serotonin signaling via 5-HT2B contributes to the progression from to fibrotic , with upregulated receptor expression in diseased liver tissues. Antagonism of 5-HT2B induces in activated stellate cells and supports hepatic regeneration in models, highlighting its potential to mitigate NASH-related scarring. Emerging research links 5-HT2B receptor signaling to through its regulation of growth factor (CCN2) production in chondrocytes, where serotonin via 5-HT2B represses CCN2 and modulates matrix remodeling.

Therapeutic potential

Current drugs and safety concerns

Several drugs that act as at the 5-HT2B receptor have been approved for clinical use but carry significant safety risks, particularly the development of (VHD). , a D2 receptor with 5-HT2B , is currently approved for treating hyperprolactinemia and has been associated with an increased risk of cardiac-valve regurgitation in long-term users. , another ergot-derived used for , was withdrawn from the market in 2007 due to its potent 5-HT2B leading to VHD. Similarly, , a serotonin releaser with indirect 5-HT2B , was banned by the FDA in 1997 after reports of VHD in patients treated for . Antagonists at the 5-HT2B receptor have also been developed for gastrointestinal and neurological indications, though their use has been limited by cardiovascular concerns. , a 5-HT4 receptor and potent 5-HT2B antagonist, was approved for with but withdrawn in following post-marketing reports of ischemic cardiovascular events; subsequent re-evaluations, including independent adjudications of , supported its re-approval in 2019 for limited use in women under 65 years without cardiovascular risk factors. , an used for prophylaxis, acts as a non-selective antagonist but has been restricted due to risks of retroperitoneal and cardiac , necessitating drug holidays every 6 months to mitigate these effects. The association between 5-HT2B receptor and VHD has established this pathway as a major safety liability in , prompting regulatory agencies like the FDA to flag it as a red flag for serotonergic compounds. Guidelines recommend routine screening for 5-HT2B during of such drugs to assess off-target effects and predict clinical risks. For patients on high-risk 5-HT2B agonists like or (prior to withdrawal), monitoring includes baseline and periodic to detect valvular abnormalities, with more frequent imaging for those on higher cumulative doses.

Emerging research applications

Recent studies have explored peripherally restricted partial agonists of the 5-HT2B receptor as a strategy for treating pulmonary arterial hypertension (PAH) while minimizing side effects. In preclinical models, the compound VU6047534, a selective with low brain penetration (brain Kp = 0.02), significantly reduced right ventricular systolic pressure (RVSP) and in both preventive and therapeutic regimens in Sugen-hypoxia mice, without inducing hallucinations or other CNS effects observed with non-restricted ligands. This approach leverages P-glycoprotein-mediated efflux to restrict activity to pulmonary vasculature, potentially offering a safer alternative for PAH management. In the realm of fibrosis therapies, next-generation selective 5-HT2B antagonists based on a methanocarba nucleoside scaffold have shown promise in preclinical models of idiopathic pulmonary fibrosis (IPF) and non-alcoholic steatohepatitis (NASH). These compounds exhibit nanomolar potency, over 30-fold selectivity against the 5-HT2C receptor, and favorable oral bioavailability, effectively reducing fibrotic progression in vivo without CNS liabilities or hERG channel inhibition. Earlier work supports the antifibrotic potential of 5-HT2B blockade, as antagonists like terguride reversed lung remodeling in IPF models by inhibiting key fibrogenic pathways. For neuropsychiatric applications, 5-HT2B antagonists have demonstrated neuroprotective effects in models by attenuating tau pathology. Postmortem analysis of cortical samples from Alzheimer's patients revealed elevated 5-HT2B receptor levels compared to controls (p = 0.039), and treatment with the selective antagonist MW071 rescued tau oligomer-induced impairments in (, p = 0.0039) and in mice (p = 0.0108). In psychedelic research for depression, 2025 designs emphasize 5-HT2A-selective agonists that avoid 5-HT2B activation to mitigate cardiac risks while preserving efficacy; for instance, LSD's rapid effects in forced swim tests were blocked by 5-HT2B antagonists, highlighting the need for biased selectivity in next-generation compounds. Emerging applications also extend to liver regeneration and cancer adjunct therapy. Antagonism of 5-HT2B signaling enhances proliferation and reduces in models, with 5-HT2B knockout mice showing accelerated recovery post-partial compared to wild-type controls. In , 5-HT2B blockade inhibits tumor cell proliferation and stromal remodeling; for example, antagonists reduced growth and fibroblast activation and , suggesting utility as an anti-proliferative adjunct in serotonin-producing cancers like small intestine .

References

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