THIORIDAZINE HYDROCHLORIDE

Details

Stereochemistry	RACEMIC
Molecular Formula	C21H26N2S2.ClH
Molecular Weight	407.035
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=NZFNXWQNBYZDAQ-UHFFFAOYSA-N

InChI=1S/C21H26N2S2.ClH/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;1H

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 290 Target ID: CHEMBL217 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12747773	Antagonist 2737	27.0 nM [Ki]
Dopamine D1 receptor 98 Target ID: CHEMBL265 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2888897	Antagonist 2737	17.3 nM [IC50]
Serotonin 2c (5-HT2c) receptor 121 Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7898773	Antagonist 2737	6.06 null [pIC50]
Serotonin 2a (5-HT2a) receptor 229 Target ID: CHEMBL224 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7898773	Antagonist 2737	6.32 null [pIC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 288 Sources: https://www.drugs.com/pro/thioridazine.html	Primary		Approved 8307	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 1670	inhibitor 1695	substrate 1168 inhibitor 1789	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1401 BCRP 678 MRP2 363 Nav1.5 95	CYP2C19 955 CYP1A2 1013

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1747	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/16382211/ Page: 4.0	no
CYP2D6 1826	inhibitor 3185 Sources: https://dmd.aspetjournals.org/content/27/9/1078.full Page: abstract	yes [IC50 2.7 uM]
BCRP 751	inhibitor 3185 Sources: https://link.springer.com/article/10.1007/s11095-009-9896-0 Page: 3.0	yes
MRP2 452	inhibitor 3185 Sources: https://link.springer.com/article/10.1007/s11095-009-9896-0 Page: 3.0	yes
P-gp 1588	inhibitor 3185 Sources: https://link.springer.com/article/10.1007/s13277-014-2278-1 Page: abstract	yes

Drug as victim

Target	Modality	Activity
CYP1A2 1013	substrate 3264 Sources: https://www.tandfonline.com/doi/abs/10.1080/00498250500158134 Page: 10.0	weak
CYP2C19 955	substrate 3264 Sources: https://www.tandfonline.com/doi/abs/10.1080/00498250500158134 Page: 10.0	weak
CYP2D6 1168	substrate 3264 Sources: https://www.tandfonline.com/doi/abs/10.1080/00498250500158134 Page: 10.0	yes
CYP3A4 1670	substrate 3264 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 98	inhibitor 1584 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603905/pdf/nihms905997.pdf Page: 4.0
hERG 1603	inhibitor 1584 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
Thioridazine incontinence.	1972 Jan 10	5066616
Thioridazine toxicity. Agranulocytosis and hepatitis with encephalopathy.	1973 Apr 23	4739612
The therapeutic use of diazepam for akathisia.	1973 Jul-Aug	4795129
Ventricular arrhythmias associated with use of thioridazine hydrochloride in alcohol withdrawal.	1973 Nov 24	4758451
Neuroleptic-induced tardiave dyskinesias in nonpsychotic patients.	1974 Apr	4816841
Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs.	1976 Feb	2004
Effect of bromocriptine mesylate on induced hyperprolactinemia in stabilized psychiatric outpatients undergoing neuroleptic treatment.	1985	4047382
Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose.	1985 Apr	3992882
Molindone hydrochloride treatment of hospitalized children with conduct disorder.	1985 Aug	3894338
Drug-induced torsade de pointes.	1985 Nov-Dec	2416504
Limited effect of magnesium sulphate on torsades de pointes ventricular tachycardia.	1986 Aug	3744606
Baclofen-induced catatonia.	1986 Dec	3805341
Tics with combined thioridazine-methylphenidate therapy: case report.	1986 Jan	3941061
Susceptibility to drug-induced hypotension in post-partum psychosis.	1986 Jan	3559152
Neurotoxicity induced by combined lithium-thioridazine treatment.	1986 Jul	3089336
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
Rapid death resulting from mesoridazine overdose.	1987 Feb	3824877
Iatrogenic torsade de pointes induced by thioridazine.	1987 Jan	3790644
[Mechanism of the development of thioridazine retinopathy].	1988 Jan	3337876
Hyperthermia, hypertension, hypertonia, and coma in a massive thioridazine overdose.	1988 Jul	3390252
A case of secondary mania.	1988 Winter	3340705
Renal and hepatic impairment in association with diclofenac administration.	1989 Jul	2602249
Myxedema coma associated with lithium therapy.	1989 Sep	2773973
Spectral electroretinography in thioridazine toxicity.	1990 Aug	2221706
Seizure promotion and protection by D-1 and D-2 dopaminergic drugs in the mouse.	1990 Aug	1977176
Persistent dystonia associated with buspirone.	1990 Dec	2247245
Neurologic approach to drug-induced movement disorders: a study of 125 patients.	1990 May	1971459
Ventricular tachycardia associated with desipramine and thioridazine.	1990 Winter	2300645
Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1.	1991 Apr 18	1826762
Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds.	2004 Oct	15671647
[Sonapax use in the clinical practice].	2005 Apr	15962598
Stable expression of constitutively activated mutant h5HT6 and h5HT7 serotonin receptors: inverse agonist activity of antipsychotic drugs.	2005 May	15821958
An incorrect diagnosis of psychosis?	2007 Apr	17392943
Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells.	2007 Mar	17175557
Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s.	2009 Oct 7	19482014
Identification of selected therapeutic agents as inhibitors of carboxylesterase 1: potential sources of metabolic drug interactions.	2010 Apr 11	20097249
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010 Dec	21158687
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
Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.	2011 Sep	21693436
Antitubercular pharmacodynamics of phenothiazines.	2013 Apr	23228936
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis.	2013 Feb	23243064
Phenothiazines inhibit hepatitis C virus entry, likely by increasing the fluidity of cholesterol-rich membranes.	2013 Jun	23529728
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 17 00:11:31 UTC 2022` Edited by `admin` on `Sat Dec 17 00:11:31 UTC 2022`
Record UNII	4WCI67NK8M
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

THIORIDAZINE HYDROCHLORIDE

Common Name

English

THIORIDAZINE HYDROCHLORIDE [USP-RS]

Common Name

English

THIORIDAZINE HYDROCHLORIDE [MART.]

Common Name

English

THIORIDAZINE HYDROCHLORIDE [JAN]

Common Name

English

THIORIDAZINE HYDROCHLORIDE [VANDF]

Common Name

English

Thioridazine hydrochloride [WHO-DD]

Common Name

English

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

Common Name

English

THIORIDAZINE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

THIORIDAZINE HCL

Common Name

English

THIORIDAZINE HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

THIORIDAZINE HYDROCHLORIDE [MI]

Common Name

English

THIORIDAZINE HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

NSC-186060

Code

English

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

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C29710