Protein / target

5-hydroxytryptamine receptor 2A

HTR2AP28223Homo sapiensSwiss-Prot
UniProt: P28223Ensembl: ENSG00000102468HGNC: HGNC:5293NCBI Gene: 3356
Clinically validated
Therapeutic maturity
59
Approved medicines
30
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding

Primary system

Nervous system

Strongest disease association

major depressive disorder

Genetic evidence · score 0.55

Therapeutic maturity

Clinically validated target

59 approved medicines against this target

Druggability

Small molecule

Open Targets tractability · Approved Drug

Clinical development

59 approved · 12 in clinical development

30 linked trials

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function

G protein-coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895, PubMed:21645528, PubMed:22300836, PubMed:35084960, PubMed:38552625). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538, PubMed:35084960). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:28129538, PubMed:35084960). HTR2A is coupled to G(q)/G(11) G alpha proteins and activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers that modulate the activity of phosphatidylinositol 3-kinase and promote the release of Ca(2+) ions from intracellular stores, respectively (PubMed:18703043, PubMed:28129538, PubMed:35084960). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538, PubMed:35084960). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction (By similarity)

Subcellular location

Cell membraneCell projection, dendriteCell projection, axonCytoplasmic vesicleMembrane, caveolaPresynapse
Domains and Gene Ontology detail (55)

Gene Ontology

  • Caxon
  • Ccaveola
  • Ccell body fiber
  • Ccytoplasmic vesicle
  • Cdendrite
  • Cdendritic shaft
  • CG protein-coupled serotonin receptor complex
  • Cglutamatergic synapse
  • Cneurofilament
  • Cneuronal cell body
  • Cplasma membrane
  • Cpostsynaptic membrane

471 aa · 53 kDa · 2 isoforms

Biological roles

Reactome v97

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Synaptic signallingUniProt · GOG protein-coupled signallingUniProt · GOMuscle contractionUniProt · GOExcitatory neurotransmissionGOImmune signallingGOApoptosis & cell deathGO
View supporting evidence

Synaptic signalling

  • ·Presynapse
  • ·glutamatergic synapse
  • ·postsynaptic membrane
  • ·presynaptic membrane

G protein-coupled signalling

  • ·G protein-coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:1…
  • ·G protein-coupled serotonin receptor complex
  • ·G protein-coupled serotonin receptor activity
  • ·G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messen…

Muscle contraction

  • ·G protein-coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:1…
  • ·artery smooth muscle contraction
  • ·urinary bladder smooth muscle contraction

Excitatory neurotransmission

  • ·glutamatergic synapse
  • ·negative regulation of synaptic transmission, glutamatergic

Immune signalling

  • ·positive regulation of cytokine production involved in immune response
  • ·positive regulation of inflammatory response

Apoptosis & cell death

  • ·positive regulation of neuron apoptotic process
View underlying pathways (2)
Serotonin receptors
G alpha (q) signalling events

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Interaction neighbourhood

STRING v12.0

Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.

GRM2HTR2CGNAQHTR2BSLC6A4CACNA1CGNASGNA11HTR1ACACNA1DHTR2A

10 strongest partners — larger node and heavier line mean higher confidence

Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.

Drugs targeting this protein

8

Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.

Risperidone
Narrow target profileApprovedAntagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving bipolar disorder, schizophrenia, aggressive behavior, autism

Direct interaction with this protein · 1 of 3 recorded protein targets — narrow recorded profile

Quetiapine Fumarate
Narrow target profileApprovedAntagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving schizophrenia, bipolar disorder, bipolar I disorder, major depressive disorder

Direct interaction with this protein · 1 of 3 recorded protein targets — narrow recorded profile

Psilocybin
Narrow target profilePhase 3Agonist

Serotonin 2a (5-HT2a) receptor agonist

Appears in clinical studies involving depressive disorder, treatment resistant depression, major depressive disorder, Abnormal emotional state

Direct interaction with this protein · Only this protein recorded as a target

volinanserin
Narrow target profilePhase 3Antagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving sleep-wake disorder, insomnia, depressive disorder, major depressive disorder

Direct interaction with this protein · Only this protein recorded as a target

Clozapine
Narrow target profileApprovedAntagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving schizophrenia, schizoaffective disorder, psychotic disorder, bipolar disorder

Direct interaction with this protein · 1 of 2 recorded protein targets — narrow recorded profile

paliperidone palmitate
Narrow target profileApprovedAntagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving schizophrenia, schizoaffective disorder, psychotic symptoms, bipolar I disorder

Direct interaction with this protein · 1 of 2 recorded protein targets — narrow recorded profile

aripiprazole
Narrow target profileApprovedAntagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving schizophrenia, major depressive disorder, bipolar disorder, Agitation

Direct interaction with this protein · 1 of 3 recorded protein targets — narrow recorded profile

olanzapine
ApprovedAntagonist

Serotonin 2a (5-HT2a) receptor antagonist

Appears in clinical studies involving bipolar disorder, schizophrenia, major depressive disorder, Agitation

Direct interaction with this protein · 1 of 5 recorded protein targets

ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.

Translational evidence

Open Targets 26

Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.

Strongest genetic associations

Human genetic evidence — the most direct causal link between this target and a disease.

major depressive disorder0.55

Genetic · overall 0.70

Highest-confidence therapeutic associations

Diseases where a drug acting on this target has already reached clinical development.

schizophrenia1.00

Clinical · overall 0.62

bipolar disorder1.00

Clinical · overall 0.61

autism1.00

Clinical · overall 0.62

psychotic disorder0.99

Clinical · overall 0.61

bipolar I disorder0.99

Clinical · overall 0.60

Highest overall evidence

Remaining associations by Open Targets' aggregated evidence score.

depressive disorder0.61

Clinical

Agitation0.60

Clinical

schizoaffective disorder0.60

Clinical

aggressive behavior0.60

Clinical

Show all associations
major depressive disorder0.70
schizophrenia0.62
autism0.62
psychotic disorder0.61
bipolar disorder0.61
depressive disorder0.61
bipolar I disorder0.60
Agitation0.60
schizoaffective disorder0.60
aggressive behavior0.60

Open Targets ranks 595 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.

Known drugs · 74 total

ZIMELDINEApproval

major depressive disorder · depressive disorder

TRIFLUOPERAZINE HYDROCHLORIDEApproval

schizophrenia · anxiety disorder · mental disorder

SB-773812Phase 2

schizophrenia

BREXPIPRAZOLEApproval

major depressive disorder · schizophrenia · psychotic disorder

HALOPERIDOL DECANOATEApproval

schizophrenia · schizoaffective disorder

TEDATIOXETINEPhase 2

major depressive disorder · generalized anxiety disorder

PALIPERIDONEApproval

schizophrenia · schizoaffective disorder · psychotic disorder

CYCLOBENZAPRINEApproval

depressive disorder · fibromyalgia · post-traumatic stress disorder

ZIPRASIDONE MESYLATEApproval

bipolar disorder

MIRTAZAPINEApproval

major depressive disorder · depressive disorder · insomnia

Tractability

SM · Approved DrugSM · Structure with LigandSM · High-Quality LigandSM · Druggable FamilyAB · UniProt loc high confAB · GO CC high confAB · UniProt SigP or TMHMMPR · Small Molecule Binder

Safety liabilities

increased pupil diameterplatelet aggregationhyperreflexiasexual dysfunctionsincreased sleepsmooth muscle contractionadverse drug reactionssweatingincreased body temperaturedecreased memoryheadachedrug abuse/dependence

Clinical trials

30

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.

Safety and Efficacy of Psilocybin for the Treatment of Headache Disorders: Sub-Study IPHASE1

COMPLETED · via Psilocybin · NCT03341689

Effects of 5-HTR2A, DRD2,and COMT Genes Polymorphisms and Drug Plasma Concentration on Antipsychotic Response to Olanzapine in Treatment of Early-onset SchizophreniaPHASE4

COMPLETED · via olanzapine · NCT02435654

Pilot Study of Psilocybin-Assisted Therapy for Demoralization in Patients Receiving Hospice Care - PATH StudyPHASE2

COMPLETED · via Psilocybin · NCT04950608

Activating Neuroplasticity to ENHANCE the Perception Box Expanding Effects of PsilocybinPHASE1

RECRUITING · via Psilocybin · NCT05866471

A Multicenter, Double-Blind, Flexible -Dose, 6-Month Trial Comparing the Efficacy and Safety of Asenapine With Olanzapine in Stable Subjects With Predominant, Persistent Negative Symptoms of Schizophrenia.PHASE3

COMPLETED · via olanzapine · NCT00145496

The Efficacy and Tolerability of Psilocybin in Participants With Treatment-Resistant Depression: a Phase 2, Randomized Feasibility StudyPHASE2

COMPLETED · via Psilocybin · NCT05029466

Show remaining trials (24)
Investigating the Therapeutic Effects of Psilocybin in Treatment-Resistant Post-Traumatic Stress DisorderPHASE2

UNKNOWN · via Psilocybin · NCT05243329

The Safety and Efficacy of Psilocybin in Participants With Treatment Resistant DepressionPHASE2

COMPLETED · via Psilocybin · NCT03775200

Long-Term Extension Study of MP-214 in Patients With SchizophreniaPHASE2/PHASE3

COMPLETED · via Risperidone · NCT01626872

Induction Protocol for Psilocybin-Assisted Therapy in Treatment-Resistant Depression (TRD): A Pilot StudyPHASE3

ACTIVE_NOT_RECRUITING · via Psilocybin · NCT06303739

Effect of Lurasidone Vs Olanzapine on Neurotrophic Biomarkers and Cardiometabolic Parameters in First Episode Untreated Schizophrenia: A Randomized, Open Label, Active Controlled StudyPHASE4

COMPLETED · via olanzapine · NCT03304457

Effects and Therapeutic Potential of Psilocybin in Alcohol DependencePHASE2

COMPLETED · via Psilocybin · NCT01534494

Comparison of Olanzapine and Lamotrigine in the Prevention of Recurrence of Depressive Episode in the Patients With Bipolar DisordersPHASE4

COMPLETED · via olanzapine · NCT01864551

Aripiprazole in At-Risk Children With Symptoms of Bipolar DisorderPHASE3

COMPLETED · via aripiprazole · NCT00194012

The Effect of MS14 in Association With Risperidone in Treatment of Schizophrenia: A Double Blind Randomized Control TrialPHASE2

UNKNOWN · via Risperidone · NCT01083381

A Fifteen-month, Prospective, Randomized, Active-controlled, Open-label, Flexible Dose Study of Paliperidone Palmitate Compared With Oral Antipsychotic Treatment in Delaying Time to Treatment Failure in Adults With Schizophrenia Who Have Been IncarceratedPHASE4

COMPLETED · via Risperidone · NCT01157351

Joining Forces: Integrating Psychotropic Medication Into the Care of People With Mental Disorders in a Prayer Camp in GhanaPHASE4

COMPLETED · via olanzapine · NCT02593734

Effectiveness, Safety and Tolerability of Flexibly Dosed Paliperidone Palmitate in Patients With Schizophrenia Previously Unsuccessfully Treated by Oral Antipsychotics and With Acute Symptom of Schizophrenia: A 13-Week, Open-label, Single-arm, Multicenter, Prospective, Interventional Study Followed by a Naturalistic Additional 1 Year Follow upPHASE4

COMPLETED · via paliperidone palmitate · NCT01685931

Comparative Effectiveness of Antipsychotic Medications in Patients With Schizophrenia (CATIE Schizophrenia Trial)PHASE4

COMPLETED · via olanzapine · NCT00014001

Seroquel (Quetiapine) Therapy for Schizophrenia and Schizoaffective Disorders and Comorbid Cocaine and/or Amphetamine Abuse/Dependence: A Comparative Study With RisperidonePHASE4

COMPLETED · via Risperidone · NCT00208143

Reducing the Abuse Liability of Prescription OpioidsEARLY_PHASE1

COMPLETED · via Risperidone · NCT04587115

Open Flexible-dose Randomized Study of the Effectiveness of Second Generation Antipsychotics in First Episode Psychosis Patients: A 1-year Follow-upPHASE4

UNKNOWN · via aripiprazole · NCT02532491

Continuation Pharmacotherapy for Agitation of DementiaPHASE2

COMPLETED · via Risperidone · NCT00073658

Olanzapine for Prevention of Chemotherapy-induced Nausea and Vomiting in Children: A Multi-Centre Feasibility StudyPHASE2

COMPLETED · via olanzapine · NCT02129478

Olanzapine Augmentation in Clozapine-resistant Schizophrenia: a Randomized Double-blind StudyPHASE4

COMPLETED · via olanzapine · NCT00918021

Effects of Psilocybin in Major Depressive DisorderPHASE2

COMPLETED · via Psilocybin · NCT03181529

A 24-month, Prospective, Randomized, Active-Controlled, Open-Label, Rater-Blinded, Multicenter, International Study of the Prevention of Relapse Comparing Long-Acting Injectable Paliperidone Palmitate to Treatment as Usual With Oral Antipsychotic Monotherapy in Adults With SchizophreniaPHASE3

COMPLETED · via paliperidone palmitate · NCT01081769

Placebo Controlled Trial of Valproate and Risperidone in Young Children With Bipolar DisordersPHASE3

COMPLETED · via Risperidone · NCT00221403

The Impact of Pre-operative Olanzapine on Quality of Recovery-40 Scores After Discharge From Ambulatory SurgeryPHASE2

COMPLETED · via olanzapine · NCT05676294

A Double-Blind, 40-Week Continuation Study Evaluating the Safety of Asenapine and Olanzapine in the Treatment of Subjects With Acute Mania Clinical Trial Protocol A7501007 (Secondary Title: ARES)PHASE3

COMPLETED · via olanzapine · NCT00159783

ClinicalTrials.gov via the drug-target graph.

Forefront confidence

Synthesis

Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.

major depressive disorderWell supported
0.92
agreement 0.82–1.00
Clinical47%Genetic35%Animal model11%Literature7%

Open Targets aggregate 0.70 · 4 independent evidence families

schizophreniaWell supported
0.77
agreement 0.61–0.92
Clinical91%Literature9%

Open Targets aggregate 0.62 · 2 independent evidence families

autismWell supported
0.76
agreement 0.60–0.92
Clinical94%Literature6%

Open Targets aggregate 0.62 · 2 independent evidence families

psychotic disorderWell supported
0.76
agreement 0.60–0.91
Clinical93%Literature7%

Open Targets aggregate 0.61 · 2 independent evidence families

bipolar disorderWell supported
0.76
agreement 0.60–0.91
Clinical96%Literature4%

Open Targets aggregate 0.61 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.

What's happening now

60

Recent activity around this target, drawn from one canonical event stream. Every item is reached through 6 drugs that target this protein, so each event is news about that drug rather than about the protein directly.

  1. Label change2026-07-01

    Label change: RISPERIDONE (ANDA076996)

    fda · regulatory · fda · via Risperidone

  2. Label change2026-06-08

    Label change: RISPERIDONE (ANDA077494)

    fda · regulatory · fda · via Risperidone

  3. Product recall2026-05-27

    Recall (Class II): ARIPIPRAZOLE

    fda · safety · fda · via aripiprazole

  4. New publication2026-01-02
    Psychological Therapy Quantity and Depressive Symptom Reduction in Psychedelic-Assisted Therapy: A Systematic Review and Meta-Analysis.

    JAMA network open · 2026 · 1 citation · Europe PMC · via Psilocybin

  5. Label change2025-11-04

    Label change: RISPERIDONE (ANDA091384)

    fda · regulatory · fda · via Risperidone

  6. Withdrawn from market2025-08-12

    Market withdrawal: Olanzapine Apotex (EMA)

    ema · market · ema · via olanzapine

  7. New publication2025-08-05
    A dose of therapy with psilocybin - A meta-analysis of the relationship between the amount of therapy hours and treatment outcomes in psychedelic-assisted therapy.

    General hospital psychiatry · 2025 · 1 citation · Europe PMC · via Psilocybin

  8. New publication2025-06-30
    Psychedelic-Assisted Therapies for Psychosocial Symptoms in Cancer: A Systematic Review and Meta-Analysis.

    Current oncology (Toronto, Ont.) · 2025 · 2 citations · Europe PMC · via Psilocybin

  9. Label change2025-06-17

    Label change: RISPERIDONE (ANDA079088)

    fda · regulatory · fda · via Risperidone

  10. New publication2025-03-03
    Psychedelic-assisted therapy: An overview for the internist.

    Cleveland Clinic journal of medicine · 2025 · 2 citations · Europe PMC · via Psilocybin

  11. New publication2025-02-28
    Prolonged adverse effects from repeated psilocybin use in an underground psychedelic therapy training program: a case report.

    BMC psychiatry · 2025 · 4 citations · Europe PMC · via Psilocybin

  12. New publication2025-02-17
    Psychedelic-assisted Therapy as a Promising Treatment for Irritable Bowel Syndrome.

    Journal of clinical gastroenterology · 2025 · 2 citations · Europe PMC · via Psilocybin

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.