Flupenthixol (T3D2920)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (8)XML
Targets (8)
Record Information
Version2.0
Creation Date2009-07-21 20:27:52 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2920
Identification
Common NameFlupenthixol
ClassSmall Molecule
DescriptionFlupentixol is an antipsychotic neuroleptic drug. It is a thioxanthene, and therefore closely related to the phenothiazines. Its primary use is as a long acting injection given two or three weekly to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness. It is a D1 and D2 receptor antagonist. It is not approved in the United States.
Compound Type
  • Amine
  • Antipsychotic Agent
  • Dopamine Antagonist
  • Drug
  • Ether
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
  • Thioxanthene
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
Depixol
Fluanxol
Flupenthixole
Flupentixol
Flupentixolo
Flupentixolum
Jexit
Chemical FormulaC23H27F3N2OS
Average Molecular Mass436.533 g/mol
Monoisotopic Mass436.180 g/mol
CAS Registry Number2709-56-0
IUPAC Name2-(4-{3-[2-(trifluoromethyl)-9,9a-dihydro-4aH-thioxanthen-9-ylidene]propyl}piperazin-1-yl)ethan-1-ol
Traditional Nameflupenthixol
SMILES[H]\C(CCN1CCN(CCO)CC1)=C1\C2C=C(C=CC2SC2=CC=CC=C12)C(F)(F)F
InChI IdentifierInChI=1/C23H27F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,20,22,29H,3,9-15H2/b18-5-
InChI KeyInChIKey=DTTVNHWDONBIKE-DVZOWYKENA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as thioxanthenes. These are organic polycyclic compounds containing a thioxanthene moiety, which is an aromatic tricycle derived from xanthene by replacing the oxygen atom with a sulfur atom.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzothiopyrans
Sub Class1-benzothiopyrans
Direct ParentThioxanthenes
Alternative Parents
Substituents
  • Thioxanthene
  • Thiochromane
  • Aryl thioether
  • N-alkylpiperazine
  • Alkylarylthioether
  • 1,4-diazinane
  • Piperazine
  • Thiopyran
  • Benzenoid
  • Tertiary aliphatic amine
  • 1,2-aminoalcohol
  • Tertiary amine
  • Azacycle
  • Alkanolamine
  • Thioether
  • Organic oxygen compound
  • Primary alcohol
  • Alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Organic nitrogen compound
  • Amine
  • Alkyl halide
  • Organopnictogen compound
  • Alkyl fluoride
  • Hydrocarbon derivative
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility0.000346 mg/ml
LogP4.51
Predicted Properties
PropertyValueSource
Water Solubility0.003 g/LALOGPS
logP4.12ALOGPS
logP3.54ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)15.59ChemAxon
pKa (Strongest Basic)8.51ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area26.71 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity120.93 m³·mol⁻¹ChemAxon
Polarizability45.28 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-052f-9676500000-6b1399e0dd965860c60c2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0kfx-7343900000-bb450af2259a54640db12017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0201900000-095389998f2b63d484e52017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0aor-1914300000-8295bd965255669954f62017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-015i-4901000000-783ed0fccbbc28c48cee2017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000i-0000900000-9ce18246bedc83edf3472017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000i-1401900000-aee927a7c2a7b4e811f12017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9201000000-b5c6ccae989978ac9b0e2017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0001900000-bd4e09974af0466a3cbe2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-052r-0016900000-5c47058a37461c2bef3d2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0zfs-2239000000-6f83d85a09b5c5a4753e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000i-0000900000-1edd1377901f279443172021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4u-0005900000-4d71ee0a497e6c0b24682021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-0295100000-6274c7e3ec4279e237fd2021-10-11View Spectrum
Toxicity Profile
Route of ExposureFairly slow and incomplete after oral administration
Mechanism of ToxicityFlupenthixol is a thioxanthene antipsychotic. The mechanism of action of Flupenthixol is not completely understood. Flupenthixol is a powerful antagonist of both D1 and D2 dopamine receptors, and an alpha-adrenergic receptor antagonist. It's antipsychotic activity is thought to be related to blocks postsynaptic dopamine receptors in the CNS.
MetabolismMainly hepatic Half Life: 19 to 39 hours
Toxicity ValuesLD50: 300 mk/kg (Oral,Mouse) (1) LD50: 791 mg/kg (Oral, Rat) (1) LD50: 87 mk/kg (Intravenous, Mouse) (1) LD50: 37 mg/kg (Intravenous, Rat) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use in the treatment of schizophrenia and depression
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00875
HMDB IDHMDB15013
PubChem Compound ID25137855
ChEMBL IDCHEMBL54661
ChemSpider IDNot Available
KEGG IDC11191
UniProt IDNot Available
OMIM ID
ChEBI ID5121
BioCyc IDNot Available
CTD IDNot Available
Stitch IDFlupenthixol
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFlupenthixol
References
Synthesis Reference

Smith Kline & French Laboratories; British Patent 925,538; May 8, 1963.
Craig, P.N. and Zirkle, C.L.; U.S. Patent 3,282,930; November 1, 1966; assigned to Smith Kline & French Laboratories.

MSDST3D2920.pdf
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Drugs.com [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. D(2) dopamine receptor
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
Molecular Weight:
50618.91 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. [11873706 ]
  3. Arnt J: Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of D-amphetamine. Eur J Pharmacol. 1995 Sep 5;283(1-3):55-62. [7498321 ]
  4. Ogren SO, Hall H, Kohler C, Magnusson O, Lindbom LO, Angeby K, Florvall L: Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain. Eur J Pharmacol. 1984 Jul 20;102(3-4):459-74. [6149133 ]
  5. Huettl P, Gerhardt GA, Browning MD, Masserano JM: Effects of dopamine receptor agonists and antagonists on catecholamine release in bovine chromaffin cells. J Pharmacol Exp Ther. 1991 May;257(2):567-74. [1674528 ]
  6. Nilsson CL, Ekman A, Hellstrand M, Eriksson E: Inverse agonism at dopamine D2 receptors. Haloperidol-induced prolactin release from GH4C1 cells transfected with the human D2 receptor is antagonized by R(-)-n-propylnorapomorphine, raclopride, and phenoxybenzamine. Neuropsychopharmacology. 1996 Jul;15(1):53-61. [8797192 ]
Target Details
2. Multidrug resistance protein 1
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Dey S, Hafkemeyer P, Pastan I, Gottesman MM: A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol. Biochemistry. 1999 May 18;38(20):6630-9. [10350482 ]
  2. Hafkemeyer P, Licht T, Pastan I, Gottesman MM: Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers. Hum Gene Ther. 2000 Mar 1;11(4):555-65. [10724034 ]
  3. Yang JM, Vassil A, Hait WN: Involvement of phosphatidylinositol-3-kinase in membrane ruffling induced by P-glycoprotein substrates in multidrug-resistant carcinoma cells. Biochem Pharmacol. 2002 Mar 1;63(5):959-66. [11911848 ]
  4. Ford JM, Bruggemann EP, Pastan I, Gottesman MM, Hait WN: Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines. Cancer Res. 1990 Mar 15;50(6):1748-56. [1968358 ]
  5. Ford JM, Yang JM, Hait WN: Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice. Cancer Res. 1991 Jan 1;51(1):67-72. [1988108 ]
Target Details
3. D(1A) dopamine receptor
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
Molecular Weight:
49292.765 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Cai G, Gurdal H, Smith C, Wang HY, Friedman E: Inverse agonist properties of dopaminergic antagonists at the D(1A) dopamine receptor: uncoupling of the D(1A) dopamine receptor from G(s) protein. Mol Pharmacol. 1999 Nov;56(5):989-96. [10531405 ]
  4. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992 Jul;49(7):538-44. [1352677 ]
Target Details
4. Alpha-1A adrenergic receptor
General Function:
Protein heterodimerization activity
Specific Function:
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.
Gene Name:
ADRA1A
Uniprot ID:
P35348
Molecular Weight:
51486.005 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Target Details
5. 5-hydroxytryptamine receptor 2A
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-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.(Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.
Gene Name:
HTR2A
Uniprot ID:
P28223
Molecular Weight:
52602.58 Da
References
  1. Reimold M, Solbach C, Noda S, Schaefer JE, Bartels M, Beneke M, Machulla HJ, Bares R, Glaser T, Wormstall H: Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol. Psychopharmacology (Berl). 2007 Feb;190(2):241-9. Epub 2006 Nov 17. [17111172 ]
Target Details
6. Muscarinic acetylcholine receptor M1
General Function:
Phosphatidylinositol phospholipase c activity
Specific Function:
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:
CHRM1
Uniprot ID:
P11229
Molecular Weight:
51420.375 Da
References
  1. Golds PR, Przyslo FR, Strange PG: The binding of some antidepressant drugs to brain muscarinic acetylcholine receptors. Br J Pharmacol. 1980 Mar;68(3):541-9. [7052344 ]
Target Details
7. Neuron-specific vesicular protein calcyon
General Function:
Clathrin light chain binding
Specific Function:
Interacts with clathrin light chain A and stimulates clathrin self-assembly and clathrin-mediated endocytosis.
Gene Name:
CALY
Uniprot ID:
Q9NYX4
Molecular Weight:
23433.49 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Target Details
8. Sigma non-opioid intracellular receptor 1
General Function:
Opioid receptor activity
Specific Function:
Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria (By similarity).
Gene Name:
SIGMAR1
Uniprot ID:
Q99720
Molecular Weight:
25127.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.0022 uMNot AvailableBindingDB 85327
References
  1. Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD: Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor. J Med Chem. 1994 Nov 25;37(24):4109-17. [7990111 ]