Identification

Name
Pipotiazine
Accession Number
DB01621
Type
Small Molecule
Groups
Approved, Investigational
Description

Pipotiazine has actions similar to those of other phenothiazines. Among the different phenothiazine derivatives, it appears to be less sedating and to have a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. However, it produces a high incidence of extra pyramidal reactions. It is used for the maintenance treatment of chronic non-agitated schizophrenic patients. Symptoms of overdose include severe extrapyramidal manifestations, hypotension, lethargy and sedation.

Structure
Thumb
Synonyms
  • Piportil
  • Pipothiazine
  • Pipotiazina
  • Pipotiazinum
Product Ingredients
IngredientUNIICASInChI Key
Pipotiazine palmitate4Q3H01QRMI37517-26-3KTOYYUONFQWSMW-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Piportil L4Solution25 mgIntramuscularSanofi Aventis1980-12-312016-08-17Canada
Piportil L4Solution50 mgIntramuscularSanofi Aventis1980-12-312017-03-30Canada
Categories
UNII
L903J9JPYV
CAS number
39860-99-6
Weight
Average: 475.667
Monoisotopic: 475.196333317
Chemical Formula
C24H33N3O3S2
InChI Key
JOMHSQGEWSNUKU-UHFFFAOYSA-N
InChI
InChI=1S/C24H33N3O3S2/c1-25(2)32(29,30)20-8-9-24-22(18-20)27(21-6-3-4-7-23(21)31-24)14-5-13-26-15-10-19(11-16-26)12-17-28/h3-4,6-9,18-19,28H,5,10-17H2,1-2H3
IUPAC Name
10-{3-[4-(2-hydroxyethyl)piperidin-1-yl]propyl}-N,N-dimethyl-10H-phenothiazine-2-sulfonamide
SMILES
CN(C)S(=O)(=O)C1=CC2=C(SC3=CC=CC=C3N2CCCN2CCC(CCO)CC2)C=C1

Pharmacology

Indication

For the maintenance treatment of chronic non-agitated schizophrenic patients.

Associated Conditions
Pharmacodynamics

Pipotiazine has actions similar to those of other phenothiazines. Among the different phenothiazine derivatives, it appears to be less sedating and to have a weak propensity for causing hypotension or potentiating the effects of CNS depressants and anesthetics. However, it produces a high incidence of extra pyramidal reactions. It reduces activity of dopamine receptors in the limbic system. Its 5-HT antagonism helps normalize dopamine activity in the cortical regions.

Mechanism of action

Pipotiazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects).

TargetActionsOrganism
AD(2) dopamine receptor
antagonist
Human
AD(1A) dopamine receptor
antagonist
Human
A5-hydroxytryptamine receptor 2A
antagonist
Human
A5-hydroxytryptamine receptor 1A
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Symptoms of overdose include severe extrapyramidal manifestations, hypotension, lethargy and sedation.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINEThe therapeutic efficacy of (1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE can be decreased when used in combination with Pipotiazine.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Pipotiazine.
2,5-Dimethoxy-4-ethylamphetaminePipotiazine may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetaminePipotiazine may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetaminePipotiazine may decrease the stimulatory activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetaminePipotiazine may decrease the stimulatory activities of 4-Bromo-2,5-dimethoxyamphetamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Pipotiazine is combined with 7-Nitroindazole.
AbirateroneThe serum concentration of Pipotiazine can be increased when it is combined with Abiraterone.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Pipotiazine.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Pipotiazine.
Food Interactions
  • Avoid alcohol
  • Take with food to decrease irritation

References

General References
  1. Bechelli LP, Ruffino-Netto A, Hetem G: A double-blind controlled trial of pipotiazine, haloperidol and placebo in recently-hospitalized acute schizophrenic patients. Braz J Med Biol Res. 1983 Dec;16(4):305-11. [PubMed:6143579]
External Links
Human Metabolome Database
HMDB0015558
KEGG Drug
D08385
PubChem Compound
62867
PubChem Substance
46508263
ChemSpider
56598
BindingDB
81798
ChEMBL
CHEMBL398880
PharmGKB
PA10158
Wikipedia
Pipotiazine
ATC Codes
N05AC04 — Pipotiazine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Unknown StatusTreatmentPsychosis Nos/Other1
Not AvailableCompletedNot AvailableBipolar Disorder (BD) / Psychotic Disorder NOS / Schizoaffective Disorders / Schizophrenic Disorders / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntramuscular25 mg
SolutionIntramuscular50 mg
Prices
Unit descriptionCostUnit
Piportil L4 50 mg/ml56.19USD ml
Piportil L4 25 mg/ml17.45USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0127 mg/mLALOGPS
logP3.94ALOGPS
logP3.13ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)17.09ChemAxon
pKa (Strongest Basic)8.86ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.09 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity134.12 m3·mol-1ChemAxon
Polarizability53.17 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9896
Blood Brain Barrier+0.9461
Caco-2 permeable-0.6479
P-glycoprotein substrateSubstrate0.7257
P-glycoprotein inhibitor IInhibitor0.774
P-glycoprotein inhibitor IINon-inhibitor0.5492
Renal organic cation transporterNon-inhibitor0.6426
CYP450 2C9 substrateNon-substrate0.6896
CYP450 2D6 substrateNon-substrate0.747
CYP450 3A4 substrateSubstrate0.5077
CYP450 1A2 substrateNon-inhibitor0.8021
CYP450 2C9 inhibitorNon-inhibitor0.8585
CYP450 2D6 inhibitorNon-inhibitor0.764
CYP450 2C19 inhibitorNon-inhibitor0.6829
CYP450 3A4 inhibitorInhibitor0.5623
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6904
Ames testNon AMES toxic0.6482
CarcinogenicityNon-carcinogens0.7615
BiodegradationNot ready biodegradable0.9723
Rat acute toxicity2.5406 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8642
hERG inhibition (predictor II)Inhibitor0.5429
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenothiazines. These are polycyclic aromatic compounds containing a phenothiazine moiety, which is a linear tricyclic system that consists of a two benzene rings joined by a para-thiazine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzothiazines
Sub Class
Phenothiazines
Direct Parent
Phenothiazines
Alternative Parents
Alkyldiarylamines / Diarylthioethers / Piperidines / Organosulfonamides / Benzenoids / 1,4-thiazines / Aminosulfonyl compounds / Trialkylamines / Azacyclic compounds / Primary alcohols
show 3 more
Substituents
Phenothiazine / Alkyldiarylamine / Diarylthioether / Aryl thioether / Tertiary aliphatic/aromatic amine / Piperidine / Organosulfonic acid amide / Benzenoid / Para-thiazine / Organic sulfonic acid or derivatives
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
References
  1. Oades RD, Rao ML, Bender S, Sartory G, Muller BW: Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy. Behav Pharmacol. 2000 Jun;11(3-4):317-30. [PubMed:11103886]
  2. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. [PubMed:11873706]
  3. Wu S, Xing Q, Gao R, Li X, Gu N, Feng G, He L: Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients. Neurosci Lett. 2005 Mar 7;376(1):1-4. Epub 2004 Dec 2. [PubMed:15694263]
  4. Wu SN, Gao R, Xing QH, Li HF, Shen YF, Gu NF, Feng GY, He L: Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. Acta Pharmacol Sin. 2006 Aug;27(8):966-70. [PubMed:16867246]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  6. Seeman P: Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses. 2010 Apr;4(1):56-73. doi: 10.3371/CSRP.4.1.5. [PubMed:20643630]
  7. Boireau A, Chambry J, Dubedat P, Farges G, Carruette AM, Zundel JL, Blanchard JC: Enhancing effect of dopamine blockers on evoked acetylcholine release in rat striatal slices: a classical D-2 antagonist response? Eur J Pharmacol. 1986 Aug 22;128(1-2):93-8. [PubMed:2875894]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Gene Name
DRD1
Uniprot ID
P21728
Uniprot Name
D(1A) dopamine receptor
Molecular Weight
49292.765 Da
References
  1. Kanba S, Suzuki E, Nomura S, Nakaki T, Yagi G, Asai M, Richelson E: Affinity of neuroleptics for D1 receptor of human brain striatum. J Psychiatry Neurosci. 1994 Jul;19(4):265-9. [PubMed:7918347]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Kusumi I, Takahashi Y, Suzuki K, Kameda K, Koyama T: Differential effects of subchronic treatments with atypical antipsychotic drugs on dopamine D2 and serotonin 5-HT2A receptors in the rat brain. J Neural Transm (Vienna). 2000;107(3):295-302. [PubMed:10821438]
  2. Yamada J, Sugimoto Y, Horisaka K: Serotonin2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibits chlorpromazine- and haloperidol-induced hypothermia in mice. Biol Pharm Bull. 1995 Nov;18(11):1580-3. [PubMed:8593484]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Cosi C, Koek W: Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT(1A) receptors expressed in HeLa cells. Eur J Pharmacol. 2001 Dec 14;433(1):55-62. [PubMed:11755134]
  2. Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verriele L, Audinot V, Millan MJ: Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol. 1998 Aug 21;355(2-3):245-56. [PubMed:9760039]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Wojcikowski J, Boksa J, Daniel WA: Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver--A comparison with other phenothiazines. Biochem Pharmacol. 2010 Oct 15;80(8):1252-9. doi: 10.1016/j.bcp.2010.06.045. Epub 2010 Jul 6. [PubMed:20615392]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Zhou SF: Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761-804. doi: 10.2165/11318070-000000000-00000. [PubMed:19902987]
  2. Bhoopathy S, Xin B, Unger SE, Karnes HT: A novel incubation direct injection LC/MS/MS technique for in vitro drug metabolism screening studies involving the CYP 2D6 and the CYP 3A4 isozymes. J Pharm Biomed Anal. 2005 Apr 1;37(4):739-49. Epub 2004 Dec 30. [PubMed:15797796]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Wojcikowski J, Boksa J, Daniel WA: Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver--A comparison with other phenothiazines. Biochem Pharmacol. 2010 Oct 15;80(8):1252-9. doi: 10.1016/j.bcp.2010.06.045. Epub 2010 Jul 6. [PubMed:20615392]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Wojcikowski J, Boksa J, Daniel WA: Main contribution of the cytochrome P450 isoenzyme 1A2 (CYP1A2) to N-demethylation and 5-sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver--A comparison with other phenothiazines. Biochem Pharmacol. 2010 Oct 15;80(8):1252-9. doi: 10.1016/j.bcp.2010.06.045. Epub 2010 Jul 6. [PubMed:20615392]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Kitamura K, Omran AA, Nagata C, Kamijima Y, Tanaka R, Takegami S, Kitade T: Effects of inorganic ions on the binding of triflupromazine and chlorpromazine to bovine serum albumin studied by spectrometric methods. Chem Pharm Bull (Tokyo). 2006 Jul;54(7):972-6. [PubMed:16819214]
  2. Rukhadze MD, Bezarashvili GS, Sidamonidze NS, Tsagareli SK: Investigation of binding process of chlorpromazine to bovine serum albumin by means of passive and active experiments. Biomed Chromatogr. 2001 Oct;15(6):365-73. [PubMed:11559920]
  3. Silva D, Cortez CM, Louro SR: Quenching of the intrinsic fluorescence of bovine serum albumin by chlorpromazine and hemin. Braz J Med Biol Res. 2004 Jul;37(7):963-8. Epub 2004 Jun 22. [PubMed:15264002]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. Bednarczyk D, Ekins S, Wikel JH, Wright SH: Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1. Mol Pharmacol. 2003 Mar;63(3):489-98. [PubMed:12606755]

Drug created on August 29, 2007 14:16 / Updated on August 02, 2018 07:50