Thioridazine

Summary

Thioridazine (CHEMBL479) is an approved small-molecule serotonergic antagonist (ATC N05AC02) targeting HTR6, HTR7, and HTR1A; indicated across 6 conditions including psychotic disorder and anxiety.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N05AC02
• Targets: 9 (HTR6, HTR7, HTR1A…)
• Indications: 6 conditions
• Clinical trials: 4
• Chemistry: 370.6 Da · C21H26N2S2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL479
Name	Thioridazine
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	5452
ChEBI	CHEBI:9566
ATC	N05AC02
Molecular formula	C21H26N2S2
Molecular weight	370.6
InChIKey	KLBQZWRITKRQQV-UHFFFAOYSA-N

SMILES: CN1CCCCC1CCN2C3=CC=CC=C3SC4=C2C=C(C=C4)SC

IUPAC name: 10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfanylphenothiazine

ChEBI definition: A phenothiazine derivative having a methylsulfanyl subsitituent at the 2-position and a (1-methylpiperidin-2-yl)ethyl] group at the N-10 position.

Pharmacological roles (ChEBI): serotonergic antagonist, H1-receptor antagonist, α-adrenergic antagonist, dopaminergic antagonist, first generation antipsychotic, EC 3.4.21.26 (prolyl oligopeptidase) inhibitor, EC 1.8.1.12 (trypanothione-disulfide reductase) inhibitor.

Also known as: Dl-thioridazine, Mellaril-s, Mellerette, Melleril, Novoridazine, Rideril, Sonapax, Thioridazine, Thioridazine prolongatum, Thioril, Tioridazina, TP-21

Parent form; salt/anhydrous children: CHEMBL1200916

Patent coverage: 5,987 distinct patent families (21,859 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 21,606 (99%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
HTR6	5-HT6 receptor	Inverse agonist	7.2	0.2%	P50406
HTR7	5-HT7 receptor	Inverse agonist	7.1	0.8%	P34969
HTR1A	5-HT1A receptor	Antagonist	7.1	0%	P08908
DRD1	D1 receptor	Antagonist	7	0%	P21728
DRD5	D5 receptor	Antagonist	5.6	0%	P21918
HRH1	H1 receptor	Antagonist	7.7	0%	P35367
KCNJ6	Kir3.2	Antagonist	4.2	0.1%	P48051
HTR2A	5-HT2A receptor	Antagonist	8	0%	P28223
HTR2C	5-HT2C receptor	Antagonist	7.3	0%	P28335

Broader ChEMBL bioactivity targets: 75 (assay-derived). Sample: Tyrosyl-DNA phosphodiesterase 1, Microtubule-associated protein tau, NPC intracellular cholesterol transporter 1, Ras-related protein Rab-9A, Pleiotropic ABC efflux transporter of multiple drugs, Muscarinic acetylcholine receptor M4, 5-hydroxytryptamine receptor 2B, Tyrosine-protein kinase Fyn, Alpha-2A adrenergic receptor, Neuronal acetylcholine receptor subunit alpha-4.

Bioactivity

ChEMBL activities: 139 potent at pChembl ≥ 5 of 158 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
HTR2A	8.9	Ki	1.25	nM	CHEMBL_ACT_7802126
CHRM1	8.77	Ki	1.69	nM	CHEMBL_ACT_7802044
P08482	8.7	IC50	2	nM	CHEMBL_ACT_353942
P43140	8.69	Ki	2.06	nM	CHEMBL_ACT_7799896
P15823	8.59	Ki	2.6	nM	CHEMBL_ACT_7799898
P61169	8.55	IC50	2.8	nM	CHEMBL_ACT_476010
ADRA1D	8.54	Ki	2.9	nM	CHEMBL_ACT_7799900
DRD3	8.47	Ki	3.36	nM	CHEMBL_ACT_7799974
P61169	8.4	IC50	4	nM	CHEMBL_ACT_353940
HTR2A	8.36	IC50	4.37	nM	CHEMBL_ACT_7802125
P15823	8.33	IC50	4.69	nM	CHEMBL_ACT_7799897
P43140	8.29	IC50	5.09	nM	CHEMBL_ACT_7799895
ADRA1D	8.23	IC50	5.89	nM	CHEMBL_ACT_7799899
CHRM5	8.18	Ki	6.64	nM	CHEMBL_ACT_7802052
CHRM1	8.15	IC50	7.02	nM	CHEMBL_ACT_7802043
DRD2	8.1	Ki	8	nM	CHEMBL_ACT_22973191
HRH1	8.07	Ki	8.41	nM	CHEMBL_ACT_7800004
CHRM5	8.03	IC50	9.25	nM	CHEMBL_ACT_7802051
DRD3	8.01	IC50	9.89	nM	CHEMBL_ACT_7799973
CHRM4	7.96	Ki	11	nM	CHEMBL_ACT_7802050
DRD2	7.92	Ki	12	nM	CHEMBL_ACT_7799972
ADRA1A	7.78	AC50	16.8	nM	CHEMBL_ACT_25138223
P15823	7.77	IC50	17	nM	CHEMBL_ACT_353943
P18901	7.76	IC50	17.3	nM	CHEMBL_ACT_476018
P08909	7.75	IC50	18	nM	CHEMBL_ACT_564088
CHRM3	7.72	Ki	19	nM	CHEMBL_ACT_7802048
HTR2A	7.66	AC50	21.9	nM	CHEMBL_ACT_25173785
HTR2C	7.64	Ki	23	nM	CHEMBL_ACT_7802130
ADRA2C	7.6	Ki	25	nM	CHEMBL_ACT_7799906
DRD2	7.57	Ki	27	nM	CHEMBL_ACT_944889

Target pathways

Aggregated over 9 target gene(s): HTR6, HTR7, HTR1A, DRD1, DRD5, HRH1, KCNJ6, HTR2A, HTR2C.

Top Reactome pathways

23 total, by targets touching each:

Pathway	Targets	Genes
Signal Transduction	5	HTR1A, HTR2A, HTR2C, HTR6, HTR7
Signaling by GPCR	5	HTR1A, HTR2A, HTR2C, HTR6, HTR7
Class A/1 (Rhodopsin-like receptors)	5	HTR1A, HTR2A, HTR2C, HTR6, HTR7
Amine ligand-binding receptors	5	HTR1A, HTR2A, HTR2C, HTR6, HTR7
Serotonin receptors	5	HTR1A, HTR2A, HTR2C, HTR6, HTR7
GPCR ligand binding	5	HTR1A, HTR2A, HTR2C, HTR6, HTR7
GPCR downstream signalling	4	HTR2A, HTR2C, HTR6, HTR7
G alpha (s) signalling events	4	DRD1, DRD5, HTR6, HTR7
G alpha (q) signalling events	3	HRH1, HTR2A, HTR2C
Dopamine receptors	2	DRD1, DRD5
Neurotransmitter receptors and postsynaptic signal transmission	1	KCNJ6
Transmission across Chemical Synapses	1	KCNJ6
Neuronal System	1	KCNJ6
Activation of G protein gated Potassium channels	1	KCNJ6
G protein gated Potassium channels	1	KCNJ6
Inwardly rectifying K+ channels	1	KCNJ6
Potassium Channels	1	KCNJ6
Histamine receptors	1	HRH1
RHOBTB3 ATPase cycle	1	HTR7
GABA receptor activation	1	KCNJ6
GABA B receptor activation	1	KCNJ6
Activation of GABAB receptors	1	KCNJ6
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	KCNJ6

Dominant GO biological processes

GO term	Targets
signal transduction	8
G protein-coupled receptor signaling pathway	8
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	7
chemical synaptic transmission	7
G protein-coupled serotonin receptor signaling pathway	5
behavioral fear response	3
serotonin receptor signaling pathway	3
adenylate cyclase-activating G protein-coupled receptor signaling pathway	3
memory	3
sensitization	3
response to cocaine	3
intracellular calcium ion homeostasis	3
phospholipase C-activating serotonin receptor signaling pathway	3
adenylate cyclase-activating serotonin receptor signaling pathway	2
positive regulation of cell population proliferation	2

Indications & clinical

Indications

6 indications (1 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
psychotic disorder	4	MONDO:0005485	EFO:0005407
anxiety	3	MONDO:0011918	EFO:0005230
dementia	3	MONDO:0001627	HP:0000726
depressive disorder	3	MONDO:0002050	MONDO:0002050
acute myeloid leukemia	1	MONDO:0018874	EFO:0000222

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 4.

Phase distribution

Phase	Trials
PHASE4	1
PHASE3	1
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02307396	PHASE4	COMPLETED	Evaluation of the Necessity of Long-term Pharmacological Treatment With Antipsychotics in Schizophrenic Patients
NCT02374567	PHASE3	TERMINATED	Pharmacovigilance in Gerontopsychiatric Patients
NCT02096289	PHASE1	COMPLETED	Safety Study of Thioridazine in Combination With Cytarabine to Treat Relapsed or Refractory Acute Myeloid Leukemia
NCT02600741	Not specified	COMPLETED	Family Intervention in Recent Onset Schizophrenia Treatment (FIRST)

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 1 clinical and 4 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

784 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
BREXPIPRAZOLE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
CLOZAPINE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
DIHYDROERGOTAMINE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
OLANZAPINE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
AMOXAPINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
CARIPRAZINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
DOXEPIN	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
FLUPHENAZINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
HALOPERIDOL	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
IMIPRAMINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
LOXAPINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
PROMAZINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
RISPERIDONE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
PENFLURIDOL	ChEMBL	Phase 2	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
RITANSERIN	ChEMBL	Phase 2	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
AMITRIPTYLINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
CYPROHEPTADINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
KETANSERIN	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
KETOTIFEN	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR2A, HTR2C, HTR6, HTR7
MAPROTILINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6
METHYSERGIDE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
MIANSERIN	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
NEFAZODONE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
QUETIAPINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
TEGASEROD	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HTR1A, HTR2A, HTR2C, HTR6, HTR7
THIOTHIXENE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
ZIPRASIDONE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
LYSERGIDE	ChEMBL	Phase 2	DRD5, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
METERGOLINE	ChEMBL	Phase 2	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
NIGULDIPINE	ChEMBL	Phase 2	DRD1, DRD5, HRH1, HTR1A, HTR2C, HTR6, HTR7
SPIPERONE	ChEMBL	Phase 2	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
Pyrazinamide	PubChem	Approved	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
DESLORATADINE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
PALIPERIDONE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR2A, HTR2C, HTR7
PRAMIPEXOLE	ChEMBL + PubChem	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR7
APOMORPHINE	ChEMBL	Phase 4 (approved)	DRD1, DRD5, HRH1, HTR1A, HTR2A, HTR2C
ASENAPINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
AZELASTINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR2A, HTR2C, HTR6, HTR7
CARVEDILOL	ChEMBL	Phase 4 (approved)	DRD1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
CINACALCET	ChEMBL	Phase 4 (approved)	HRH1, HTR1A, HTR2A, HTR2C, HTR6, HTR7
CISAPRIDE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR7
CLEMASTINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
DIBENZEPIN	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR6, HTR7
EBASTINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
ILOPERIDONE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
LURASIDONE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR7
METHYLERGONOVINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
MIRTAZAPINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR7
NORTRIPTYLINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
PERGOLIDE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
PIMOZIDE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
PROCHLORPERAZINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
PROMETHAZINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
SERTINDOLE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
SUNITINIB	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6
TERFENADINE	ChEMBL	Phase 4 (approved)	DRD1, HRH1, HTR1A, HTR2A, HTR2C, HTR6