Back to discover

Protein / target

Histamine H3 receptor

Encoded byHRH3Q9Y5N1Homo sapiensSwiss-Prot
UniProt: Q9Y5N1Ensembl: ENSG00000101180HGNC: HGNC:5184NCBI Gene: 11255
Clinically validated
Therapeutic maturity
3
Approved medicines
Open Targets target-level
18
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

Neurotransmitter receptor

Strongest disease association

Narcolepsy

Via encoding gene HRH3 · Clinical evidence · score 0.51

Therapeutic position

Established drug target

Small molecules

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 overview

The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system.

View complete UniProt function annotation

The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization

Subcellular location

Cell membrane
Domains and Gene Ontology detail (11)

Gene Ontology

  • Cdendrite
  • Cplasma membrane
  • Cpresynapse
  • Csynapse
  • Fhistamine receptor activity
  • Fneurotransmitter receptor activity
  • Padenylate cyclase-activating G protein-coupled receptor signaling pathway
  • Padenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway
  • Pchemical synaptic transmission
  • PG protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
  • Pneurotransmitter secretion

445 aa · 49 kDa · 7 isoforms

Biological roles

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

Synaptic signallingGOG protein-coupled signallingGO
View supporting evidence

Synaptic signalling

  • ·presynapse
  • ·synapse
  • ·neurotransmitter receptor activity
  • ·chemical synaptic transmission

G protein-coupled signalling

  • ·adenylate cyclase-activating G protein-coupled receptor signaling pathway
  • ·adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway
  • ·G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messen…

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

Drugs targeting this protein

1

How approved and investigational drugs engage this protein — mechanism and action type, direct vs complex targeting, and how broadly each acts across other targets. A drug-first view (the section above groups the approved ones disease-first); direct binders with few recorded targets are listed first.

pitolisant
Narrow target profileApprovedInverse agonist

Histamine H3 receptor inverse agonist

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

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

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene HRH3

Gene-level evidence surfaced through the gene HRH3that encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Narcolepsy
0.64Moderately supported

Clinical evidence dominant · Open Targets 0.51

Sleep Apnea, Obstructive
0.60Moderately supported

Clinical evidence dominant · Open Targets 0.49

Narcolepsy-cataplexy syndrome
0.57Moderately supported

Clinical evidence dominant · Open Targets 0.46

Disorders of Excessive Somnolence
0.46Limited support

Clinical evidence dominant · Open Targets 0.37

Prader-Willi syndrome
0.42Limited support

Clinical evidence dominant · Open Targets 0.33

View evidence synthesis (5)
NarcolepsyModerately supported
0.64
agreement 0.48–0.79
Clinical97%Literature3%

Open Targets aggregate 0.51 · 2 independent evidence families

Sleep Apnea, ObstructiveModerately supported
0.60
agreement 0.45–0.76
Clinical99%Literature1%

Open Targets aggregate 0.49 · 2 independent evidence families

Narcolepsy-cataplexy syndromeModerately supported
0.57
agreement 0.42–0.73
Clinical98%Literature2%

Open Targets aggregate 0.46 · 2 independent evidence families

Disorders of Excessive SomnolenceLimited support
0.46
agreement 0.30–0.61
Clinical99%Literature1%

Open Targets aggregate 0.37 · 2 independent evidence families

Prader-Willi syndromeLimited support
0.42
agreement 0.26–0.57
Clinical96%Literature4%

Open Targets aggregate 0.33 · 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 per-type scores above show the calculation.

Show all associations
Narcolepsy0.51
Sleep Apnea, Obstructive0.49
Narcolepsy-cataplexy syndrome0.46
Neurodegenerative Diseases0.37
Disorders of Excessive Somnolence0.37
Prader-Willi syndrome0.33
Schizophrenia0.31

Drug development

16 compounds recorded · 3 approved · 13 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 1 drug that targets this protein in Forefront's canonical graph: these count different sets and are not a subset relation.

View all recorded compounds (10)
GSK189254Phase 2
BETAHISTINEApproval
BAVISANTPhase 2
PITOLISANT HYDROCHLORIDEApproval
SUVN-G3031Phase 3
CIPRALISANTPhase 2
GSK239512Phase 2
PITOLISANTApproval
GSK-1004723Phase 2
MK-0249Phase 2

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small molecules — Strong

Approved Drug and Structure with Ligand support this modality.

Antibodies — Emerging

Feasibility evidence (go cc high conf and uniprot loc med conf) — no clinical-stage drug of this modality recorded.

Protein degraders — Emerging

Feasibility evidence (small molecule binder) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (8)
SM · Approved DrugSM · Structure with LigandSM · High-Quality LigandSM · Druggable FamilyAB · GO CC high confAB · UniProt loc med confAB · UniProt SigP or TMHMMPR · Small Molecule Binder

Raw Open Targets tractability assessment buckets, by modality.

Clinical trials

18

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein. Ranked by active status, then clinical phase and recency, and spread across the targeting drugs.

An Open-Label Study to Evaluate Safety of Pitolisant in Participants With Prader-Willi SyndromePHASE3

ENROLLING_BY_INVITATION · via pitolisant · NCT07219485

A Phase 3, Randomized, Double-Blind, Placebo-controlled, Efficacy and Safety Study of Pitolisant Followed by an Open-Label Extension in Patients With Prader-Willi SyndromePHASE3

RECRUITING · via pitolisant · NCT06366464

An Exploratory, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Effect and Safety of Pitolisant in Children and Adolescents With Autism Spectrum DisordersPHASE2

ACTIVE_NOT_RECRUITING · via pitolisant · NCT05953389

Open Label Assessment of Pitolisant (Wakix) as Adjunct Therapy for Patients With Refractory Restless Legs SyndromePHASE4

UNKNOWN · via pitolisant · NCT05581576

View all trials (14)
An Open-Label Study to Evaluate the Long-Term Safety and Effectiveness of Pitolisant in Adult Patients With Idiopathic Hypersomnia Who Completed Study HBS-101-CL-010PHASE3

COMPLETED · via pitolisant · NCT05458128

A Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Study to Evaluate the Efficacy and Safety of Pitolisant in the Treatment of Excessive Daytime Sleepiness in Patients With Obstructive Sleep ApneaPHASE3

COMPLETED · via pitolisant · NCT05223166

Double Blind, Multicentre, Randomized, Placebo-controlled Trial to Evaluate Safety and Efficacy of Pitolisant in Children From 6 to Less Than 18 Years With Narcolepsy With/Without Cataplexy, Followed by a Prolonged Open-label PeriodPHASE3

COMPLETED · via pitolisant · NCT02611687

Efficacy and Safety of Pitolisant (BF2.649) in the Treatment of Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea Syndrome, Treated or Not by Nasal Continuous Positive Airway Pressure, But Still Complaining of Excessive Daytime SleepinessPHASE3

COMPLETED · via pitolisant · NCT02739568

A Randomized, Double Blind Study Comparing Pitolisant (BF2.649) to Placebo in Two Parallel Groups on the Weekly Frequency of Cataplexy Attacks and Excessive Daytime Sleepiness in Narcoleptic Patients With Cataplexy.PHASE3

COMPLETED · via pitolisant · NCT01800045

Efficacy and Safety of Pitolisant (BF2.649) in the Treatment of Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnoea Syndrome, Treated or Not by Nasal Continuous Positive Airway Pressure, But Still Complaining of Excessive Daytime SleepinessPHASE3

WITHDRAWN · via pitolisant · NCT02978651

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular Symptoms in Patients With Myotonic Dystrophy Type 1, Followed by an Open-Label ExtensionPHASE2

COMPLETED · via pitolisant · NCT04886518

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label ExtensionPHASE2

COMPLETED · via pitolisant · NCT04257929

A Multisite Randomized, Double-Blind, Placebo-Controlled Trial Evaluating Pitolisant (BF2.649) For Alcohol Use Disorder TreatmentPHASE2

WITHDRAWN · via pitolisant · NCT02800083

The Effects of the Histamine-3 Receptor Inverse Agonist Pitolisant on Alcohol Self-Administration in Heavy DrinkersPHASE1

TERMINATED · via pitolisant · NCT04596267

A Randomized, Double-Blind, Placebo-Controlled Insulin Tolerance Test Study to Assess the Safety, Tolerability, and Pharmacodynamics OF Pitolisant in Patients With Type 1 DiabetesPHASE1

TERMINATED · via pitolisant · NCT04026750

A Randomized, Double-Blind, Active- and Placebo-Controlled, Single-Dummy, 4-Way Crossover Study to Determine the Abuse Potential of Pitolisant Compared to Phentermine and Placebo, in Healthy, Non-Dependent Recreational Stimulant UsersPHASE1

COMPLETED · via pitolisant · NCT03152123

An Open Label, Single-Period Repeated Dose Study Designed to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-Pitolisant, at Steady-State Conditions, in Healthy CYP2D6 Genotyped Male SubjectsPHASE1

COMPLETED · via pitolisant · NCT02929342

An fMRI Investigation of the Effects of Selective Histamine-3 Receptor Antagonism on Cognitive and Emotional Processing in Healthy IndividualsNA

COMPLETED · via pitolisant · NCT05849675

ClinicalTrials.gov via the drug-target graph.

What's happening now

4

Recent therapeutic activity around this target — regulatory actions, clinical trials and safety signals for a drug that targets this protein, plus publications where such a drug is a genuine subject. Every item is reached indirectly through the drug, not the protein itself; incidental mentions (a paper that merely measures a drug) and press items are excluded.

  1. Regulatory approval2026-08-14

    Approval: PITOLISANT (ANDA218846)

    fda · regulatory · fda · via pitolisant

  2. Regulatory approval2026-08-14

    Approval: PITOLISANT (ANDA218873)

    fda · regulatory · fda · via pitolisant

  3. Regulatory approval2021-09-01

    Approval: Ozawade (EMA)

    ema · regulatory · ema · via pitolisant

  4. Regulatory approval2016-03-31

    Approval: Wakix (EMA)

    ema · regulatory · ema · via pitolisant

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.