THIORIDAZINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C21H26N2S2
Molecular Weight	370.575
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CSC1=CC2=C(SC3=C(C=CC=C3)N2CCC4CCCCN4C)C=C1

InChI

InChIKey=KLBQZWRITKRQQV-UHFFFAOYSA-N

InChI=1S/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3

HIDE SMILES / InChI

Molecular Formula	C21H26N2S2
Molecular Weight	370.575
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.drugs.com/pro/thioridazine.html

Thioridazine (Mellaril or Melleril) is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. Thioridazine primary use in medicine was the treatment of schizophrenia. Thioridazine was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia, but chronic use of thioridazine and other antipsychotics in people with dementia is not recommended. Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies. It has a higher propensity for causing anticholinergic side effects coupled with a lower propensity for causing extrapyramidal side effects and sedation than chlorpromazine but also has a higher incidence of hypotension and cardiotoxicity. It is also known to possess a relatively high liability for causing orthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics, it has a relatively high liability for causing prolactin elevation. It is the moderate risk of causing weight gain.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Potency
Dopamine D2 receptor 297 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12747773	Antagonist 2778	27.0 nM [Ki]
Dopamine D1 receptor 101 Target ID: CHEMBL265 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2888897	Antagonist 2778	17.3 nM [IC50]
Serotonin 2c (5-HT2c) receptor 124 Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7898773	Antagonist 2778	6.06 null [pIC50]
Serotonin 2a (5-HT2a) receptor 231 Target ID: CHEMBL224 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7898773	Antagonist 2778	6.32 null [pIC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 298 Sources: https://www.drugs.com/pro/thioridazine.html	Primary		Approved 8429	MELLARIL-S Approved Use Thioridazine hydrochloride tablets are indicated for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life threatening, proarrhythmic effects with thioridazine treatment, thioridazine hydrochloride tablets should be used only in patients who have failed to respond adequately to treatment with appropriate courses of other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with thioridazine hydrochloride tablets, it is strongly recommended that a patient be given at least two trials, each with a different antipsychotic drug product, at an adequate dose, and for an adequate duration (see WARNINGS and CONTRAINDICATIONS). However, the prescriber should be aware that thioridazine hydrochloride tablets have not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown. Launch Date 2.77516812E11

C_max

Value	Dose	Co-administered	Analyte	Population
131 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10952475	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		THIORIDAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
117 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2007317	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		THIORIDAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
1338 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10952475	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		THIORIDAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
709 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2007317	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		THIORIDAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
12.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10952475	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		THIORIDAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2007317	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		THIORIDAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/cps-_monographs/CPS-_(General_Monographs-_M)/MELLARIL.html			THIORIDAZINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
800 mg 1 times / day multiple, oral Recommended Dose: 800 mg, 1 times / day Route: oral Route: multiple Dose: 800 mg, 1 times / day Co-administed with:: lithium Sources: https://pubmed.ncbi.nlm.nih.gov/6145728	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/6145728	Disc. AE: Torsade de pointes... AEs leading to discontinuation/dose reduction: Torsade de pointes (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/6145728
400 mg 1 times / day multiple, oral Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/646545	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/646545	Disc. AE: Hyperthermia malignant... AEs leading to discontinuation/dose reduction: Hyperthermia malignant (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/646545

AEs

AE	Significance	Dose	Population
Torsade de pointes	1 patient Disc. AE	800 mg 1 times / day multiple, oral Recommended Dose: 800 mg, 1 times / day Route: oral Route: multiple Dose: 800 mg, 1 times / day Co-administed with:: lithium Sources: https://pubmed.ncbi.nlm.nih.gov/6145728	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/6145728
Hyperthermia malignant	1 patient Disc. AE	400 mg 1 times / day multiple, oral Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/646545	unhealthy Health Status: unhealthy Sources: https://pubmed.ncbi.nlm.nih.gov/646545

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 BCRP 699 MRP2 383 Nav1.5 97	CYP2C19 991 CYP1A2 1054

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16382211/ Page: 4.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/27/9/1078.full Page: abstract	yes [IC50 2.7 uM]
BCRP 773	inhibitor 3277 Sources: https://link.springer.com/article/10.1007/s11095-009-9896-0 Page: 3.0	yes
MRP2 475	inhibitor 3277 Sources: https://link.springer.com/article/10.1007/s11095-009-9896-0 Page: 3.0	yes
P-gp 1650	inhibitor 3277 Sources: https://link.springer.com/article/10.1007/s13277-014-2278-1 Page: abstract	yes

Drug as victim

Target	Modality	Activity
CYP1A2 1054	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.1080/00498250500158134 Page: 10.0	weak
CYP2C19 991	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.1080/00498250500158134 Page: 10.0	weak
CYP2D6 1217	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.1080/00498250500158134 Page: 10.0	yes
CYP3A4 1737	substrate 3367 Sources: https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.2007.03021.x Page: 3.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Nav1.5 100	inhibitor 1626 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603905/pdf/nihms905997.pdf Page: 4.0
hERG 1647	inhibitor 1626 Sources: https://physoc.onlinelibrary.wiley.com/doi/pdfdirect/10.14814/phy2.14385 Page: 4.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:48566	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:48566
ChemicalBook	CB4256836	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4256836
MolPort	MolPort-001-727-928	https://www.molport.com/shop/molecule-link/MolPort-001-727-928
eMolecules	595203	https://www.emolecules.com/cgi-bin/more?vid=595203

PubMed

Title	Date	PubMed
Recurrent major ventricular arrhythmias associated with thioridazine therapy.	1971 Nov	5113695
Thioridazine in schizophrenia.	1971 Sep 20	5109828
Letter: Acute hypotension from thioridazine.	1975 Dec 29	1242767
Drug-induced dystonia.	1975 May	1119613
Neurotoxicity with combined use of lithium and thioridazine.	1979 Mar	106047
Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose.	1985 Apr	3992882
Drug-induced torsade de pointes.	1985 Nov-Dec	2416504
Limited effect of magnesium sulphate on torsades de pointes ventricular tachycardia.	1986 Aug	3744606
Susceptibility to drug-induced hypotension in post-partum psychosis.	1986 Jan	3559152
Drug-induced dystonia in neuronal ceroid-lipofuscinosis.	1986 Jul-Aug	3508694
Haloperidol versus thioridazine in the treatment of behavioral symptoms in senile dementia of the Alzheimer's type: preliminary findings.	1986 Jun	3711028
Tourette-like syndrome following low dose short-term neuroleptic treatment.	1986 May	3459568
Neuroleptic-induced tics in two hyperactive children.	1986 Sep	2875666
Hyperthermia, hypertension, hypertonia, and coma in a massive thioridazine overdose.	1988 Jul	3390252
Renal and hepatic impairment in association with diclofenac administration.	1989 Jul	2602249
Prolonged fever without extrapyramidal symptoms during neuroleptic treatment.	1989 Jun	2738187
Seizure promotion and protection by D-1 and D-2 dopaminergic drugs in the mouse.	1990 Aug	1977176
Neurologic approach to drug-induced movement disorders: a study of 125 patients.	1990 May	1971459
[Ventricular arrhythmia following thioridazine poisoning].	1991 Apr	2053762
Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1.	1991 Apr 18	1826762
Transient cardiac pacing is insufficiently used to treat arrhythmia associated with thioridazine.	1992	1304415
[Iatrogenic torsade de pointes induced by thioridazine].	1992 Jun	1407620
Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.	2000 Apr	10780978
The effects of sodium bicarbonate on thioridazine-induced cardiac dysfunction in the isolated perfused rat heart.	2001 Apr	11308123
Thioridazine (Mellaril) and mesoridazine (Serentil): prolongation of the QTc interval.	2001 Jan 9	11202679
Antipsychotic-induced extrapyramidal syndromes. Risperidone compared with low- and high-potency conventional antipsychotic drugs.	2001 Jul	11549212
ANCA-positive vasculitis induced by thioridazine: confirmed by rechallenge.	2002 Dec	12452885
Melleril: gone forever!	2002 Feb	11885828
Reduced bone mineral density in patients with schizophrenia receiving prolactin raising anti-psychotic medication.	2003 Dec	14870961
Psychotropic drugs and fatal pulmonary embolism.	2003 Dec	14762980
Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia.	2003 Dec 15	14678746
Olanzapine in the treatment-resistant, combat-related PTSD--a series of case reports.	2003 May	12752037
Physical health monitoring of patients with schizophrenia.	2004 Aug	15285957
Invited review: fluphenazine augments retinal oxidative stress.	2005 Aug	16117689
Stable expression of constitutively activated mutant h5HT6 and h5HT7 serotonin receptors: inverse agonist activity of antipsychotic drugs.	2005 May	15821958
[Polymorphic ventricular tachycardia of torsade de pointes type in patient with schizophrenia treated with thioridazine].	2006 Dec	18634530
Searching for new antimalarial therapeutics amongst known drugs.	2006 Jun	16882315
[Trazodone for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease: a retrospective study focused on the aggression and negativism in caregiving situations].	2006 Jun	16856516
An incorrect diagnosis of psychosis?	2007 Apr	17392943
Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.	2007 Mar	17175557
[Repercussions of the withdrawal of thioridazine].	2008 May-Jun	18478459
QT alterations in psychopharmacology: proven candidates and suspects.	2010 Jan	20210726
Effects of K openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs.	2010 Jul	20636881
A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3'-kinase (PI3K)/AKT pathway in ovarian cancer cells.	2011 Jan	21035837
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
Comparison of a genomic and a multiplex cell imaging approach for the detection of phospholipidosis.	2011 Oct	21515356
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved.	2013 Jun	23397584

Patents

Sample Use Guides

In Vivo Use Guide

The usual starting dose for adult schizophrenic patients is 50 mg to 100 mg three times a day, with a gradual increment to a maximum of 800 mg daily if necessary. Once effective control of symptoms has been achieved, the dosage may be reduced gradually to determine the minimum maintenance dose. The total daily dosage ranges from 200 mg to 800 mg, divided into two to four doses. For pediatric patients with schizophrenia who are unresponsive to other agents, the recommended initial dose is 0.5 mg/kg/day given in divided doses. Dosage may be increased gradually until optimum therapeutic effect is obtained or the maximum dose of 3 mg/kg/day has been reached.

Route of Administration: Oral

In Vitro Use Guide

Slices of female Wistar rats frontal cortex were prepared by 350 x 350-/.tm crosschopping. These were preincubated for 1 h in Krebsbicarbonate buffer at 37°C in the presence of O2/CO2 (95:5). Aliquots of gravity-packed slices (50 mkl) were dispensed into 13 x 100 glass tubes containing 250 mk1 of 5 mkCi [3H]myo-inositol (Amersham, Les Ulis, France; specific activity 80-120 Ci/mmol) and, after 20 min incubation, antagonist (Thioridazine) or buffer, each containing pargyline and lithium chloride (final concentrations 10 mkM and 10 mM) were added and incubation continued for 10 min. Serotonin (0.6 mkM final) or buffer was added for a stimulation period of 60 min. The reaction was stopped by three volumes of chloroform/methanol (1:2). Extraction and separation of phosphoinositol was by anion-exchange chromatography

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:30:45 UTC 2023` Edited by `admin` on `Sat Dec 16 16:30:45 UTC 2023`
Record UNII	N3D6TG58NI
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

THIORIDAZINE

Official Name

English

Thioridazine [WHO-DD]

Common Name

English

NOVORIDAZINE

Brand Name

English

MELLARIL-S

Brand Name

English

THIORIDAZINE [MART.]

Common Name

English

THIORIDAZINE [USAN]

Common Name

English

THIORIL

Brand Name

English

MELLERETTE

Common Name

English

(±)-THIORIDAZINE

Common Name

English

DL-THIORIDAZINE

Common Name

English

TP-21

Code

English

THIORIDAZINE PROLONGATUM

Common Name

English

thioridazine [INN]

Common Name

English

THIORIDAZINE [VANDF]

Common Name

English

THIORIDAZINE [EP MONOGRAPH]

Common Name

English

THIORIDAZINE [HSDB]

Common Name

English

THIORIDAZINE [USP MONOGRAPH]

Common Name

English

THIORIDAZINE [MI]

Common Name

English

SONAPAX

Common Name

English

MELLARIL

Brand Name

English

10-[2-(1-Methyl-2-piperidyl)ethyl]-2-(methylthio)phenothiazine

Systematic Name

English

THIORIDAZINE [USP-RS]

Common Name

English

THIORIDAZINE [ORANGE BOOK]

Common Name

English

10H-PHENOTHIAZINE, 10-(2-(1-METHYL-2-PIPERIDINYL)ETHYL)-2-(METHYLTHIO)-

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000007544