Identification

Name
Pipamperone
Accession Number
DB09286
Type
Small Molecule
Groups
Investigational
Description

Pipamperone is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia. It was discovered at Janssen Pharmaceutica in 1961, and entered clinical trials in the United States in 1963 [11, 15].

In an effort to improve Haloperidol's pharmacological effects, Janssen discovered that pipamperone, an agent whose pharmacological profile was distinct from haloperidol and all other known antipsychotic drugs at this time, had significant anti-tryptamine activity. Some studies suggest pipamperone was the first atypical antipsychotic. Interestingly, when Risperidone was created, Janssen suggested it was a more potent version of pipamperone. Synthesized in the year 1984, risperidone’s pharmacological properties were similar to pipamperone’s in that both block more serotonin more potently than dopamine [15].

Structure
Thumb
Synonyms
  • Carpiperone
  • Floropipamide
  • Fluoropipamide
  • pipamperona
Product Ingredients
IngredientUNIICASInChI Key
Pipamperone hydrochlorideIT085U64JB2448-68-2BMXXSXQVMCXGJM-UHFFFAOYSA-N
International/Other Brands
Dipiperal / Dipiperon / Piperonil / Piperonyl / Propitan / Propitan 10%
Categories
UNII
5402501F0W
CAS number
1893-33-0
Weight
Average: 375.488
Monoisotopic: 375.232205381
Chemical Formula
C21H30FN3O2
InChI Key
AXKPFOAXAHJUAG-UHFFFAOYSA-N
InChI
InChI=1S/C21H30FN3O2/c22-18-8-6-17(7-9-18)19(26)5-4-12-24-15-10-21(11-16-24,20(23)27)25-13-2-1-3-14-25/h6-9H,1-5,10-16H2,(H2,23,27)
IUPAC Name
1'-[4-(4-fluorophenyl)-4-oxobutyl]-[1,4'-bipiperidine]-4'-carboxamide
SMILES
NC(=O)C1(CCN(CCCC(=O)C2=CC=C(F)C=C2)CC1)N1CCCCC1

Pharmacology

Indication

Treatment of chronic psychoses and states of aggressiveness of various origins [12].

Pharmacodynamics

Pipamperone is an antipsychotic medication that has sedative effects, which may be beneficial in the management of agitation and disordered sleep [8]. Pipamperone, showing antidopaminergic and anti-serotonergic properties, has been noted for its anti- agitation effects and for its ability to normalize sleep rhythms in psychiatric patients [5]. One study showed that pipamperone increased the expression of D4 (dopaminergic) receptors, explaining its helpfulness in decreasing positive psychotic symptoms, such as delusions and hallucinations [19].

Mechanism of action

Pipamperone binds mainly to 5-HT2A receptors, with a nearly equal affinity to D4 receptors and a moderate affinity for 5-HT2C, D2, D3, 1- and 2B-adrenoceptors [5].

This drug is a selective 5-HT2A, D1 and D4 antagonist [13]. Extrapyramidal adverse effects also appear to be limited in pipamperone treatment compared to traditional antipsychotic medications due to its high receptor selectivity [11].

Pipamperone has a 15-fold higher affinity for D4 than D2 receptors. It has been suggested that D4 receptors may play a role in the modulation of GABAergic neuronal activity by dopamine [5].

TargetActionsOrganism
UD(2) dopamine receptor
antagonist
Human
U5-hydroxytryptamine receptor 2A
agonist
Human
UAlpha-1 adrenergic receptors
antagonist
Human
UD(4) dopamine receptor
antagonist
Human
UD(1A) dopamine receptor
antagonist
Human
UD(3) dopamine receptorNot AvailableHuman
U5-hydroxytryptamine receptor 2BNot AvailableHuman
UAlpha-2A adrenergic receptor
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Pipamperone is metabolised in the liver [11].

Route of elimination

Mainly via the kidneys [11]

Half life

17-26h [18]

Clearance
Not Available
Toxicity

Ld50 in rats, 48 mg/kg [16]. Prolonged Qtc interval. Monitoring with regular ECGs is recommended [20].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Pipamperone is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Pipamperone is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Pipamperone.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Pipamperone is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when 3,4-Methylenedioxyamphetamine is combined with Pipamperone.
3,5-DinitrocatecholThe therapeutic efficacy of Pipamperone can be decreased when used in combination with 3,5-Dinitrocatechol.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Pipamperone.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Pipamperone is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Pipamperone.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Pipamperone is combined with 5-methoxy-N,N-dimethyltryptamine.
Food Interactions
Not Available

References

General References
  1. Prinssen EP, Koek W, Kleven MS: The effects of antipsychotics with 5-HT(2C) receptor affinity in behavioral assays selective for 5-HT(2C) receptor antagonist properties of compounds. Eur J Pharmacol. 2000 Jan 24;388(1):57-67. [PubMed:10657547]
  2. Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL: Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences. J Pharmacol Exp Ther. 1996 Feb;276(2):720-7. [PubMed:8632342]
  3. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [PubMed:8935801]
  4. Wade AG, Crawford GM, Nemeroff CB, Schatzberg AF, Schlaepfer T, McConnachie A, Haazen L, Buntinx E: Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response. Psychol Med. 2011 Oct;41(10):2089-97. doi: 10.1017/S0033291711000158. Epub 2011 Feb 25. [PubMed:21349239]
  5. Gareri P, De Fazio P, Stilo M, Ferreri G, De Sarro G: Conventional and atypical antipsychotics in the elderly : a review. Clin Drug Investig. 2003;23(5):287-322. [PubMed:17535043]
  6. Van Craenenbroeck K, Gellynck E, Lintermans B, Leysen JE, Van Tol HH, Haegeman G, Vanhoenacker P: Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor. Life Sci. 2006 Dec 3;80(1):74-81. doi: 10.1016/j.lfs.2006.08.024. Epub 2006 Aug 25. [PubMed:16978659]
  7. Wijma RA, van der Nagel BC, Dierckx B, Dieleman GC, Touw DJ, van Gelder T, Koch BC: Identification and quantification of the antipsychotics risperidone, aripiprazole, pipamperone and their major metabolites in plasma using ultra-high performance liquid chromatography-mass spectrometry. Biomed Chromatogr. 2016 Jun;30(6):794-801. doi: 10.1002/bmc.3610. Epub 2015 Oct 8. [PubMed:26447610]
  8. Squelart P, Saravia J: Pipamperone (Dipiperon), a useful sedative neuroleptic drug in troublesome chronic psychotic patients. Acta Psychiatr Belg. 1977 Mar-Apr;77(2):284-93. [PubMed:906888]
  9. Pipamperone [Link]
  10. The Treatment of Autism with Pipamperone [Link]
  11. Pipamperone [Link]
  12. Pipamperone: International drug information [Link]
  13. Low dose pipamperone in treatment mood disorders [Link]
  14. Pipamperone dihydrochloride [Link]
  15. The Pharmacological Role and Clinical Applications of Antipsychotics’ Active Metabolites: Paliperidone versus Risperidone [Link]
  16. Pipamerone [Link]
  17. Pipamperone and increased excercise/weight [Link]
  18. Current antipsychotics [Link]
  19. Use of pipamperone and a d2-receptor antagonist or a serotonin/dopamin antagonist for the treatment of psychotic disorders [Link]
  20. PP232—Acute toxicity profile of pipamperone in overdose: A consecutive case series [Link]
External Links
KEGG Drug
D02622
PubChem Compound
4830
PubChem Substance
310265179
ChemSpider
4664
BindingDB
81483
ChEBI
78549
ChEMBL
CHEMBL440294
Wikipedia
Pipamperone
ATC Codes
N05AD05 — Pipamperone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentChronic Schizophrenia / Schizoaffective Disorders1
2CompletedTreatmentDepression1
3CompletedTreatmentMajor Depressive Disorder (MDD)1
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>254https://www.trc-canada.com/product-detail/?P475200
water solubilitysoluble in methanolhttps://www.trc-canada.com/product-detail/?P475200
logP2.02https://comptox.epa.gov/dashboard/dsstoxdb/results?search=Pipamperone
Predicted Properties
PropertyValueSource
Water Solubility0.182 mg/mLALOGPS
logP2.32ALOGPS
logP1.87ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)15.94ChemAxon
pKa (Strongest Basic)8.69ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area66.64 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity105.1 m3·mol-1ChemAxon
Polarizability41.16 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 alkyl-phenylketones. These are aromatic compounds containing a ketone substituted by one alkyl group, and a phenyl group.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbonyl compounds
Direct Parent
Alkyl-phenylketones
Alternative Parents
Phenylbutylamines / Butyrophenones / Piperidinecarboxamides / Aryl alkyl ketones / Benzoyl derivatives / Aminopiperidines / Fluorobenzenes / Aryl fluorides / Gamma-amino ketones / Trialkylamines
show 6 more
Substituents
Alkyl-phenylketone / Butyrophenone / Phenylbutylamine / Piperidinecarboxamide / Benzoyl / Aryl alkyl ketone / Fluorobenzene / 4-aminopiperidine / Halobenzene / Aryl fluoride
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, tertiary amino compound, monocarboxylic acid amide, aromatic ketone, bipiperidines (CHEBI:78549)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [PubMed:8935801]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
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. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [PubMed:8935801]
Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
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) prot...

Components:
References
  1. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [PubMed:8935801]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Sh3 domain binding
Specific Function
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins ...
Gene Name
DRD4
Uniprot ID
P21917
Uniprot Name
D(4) dopamine receptor
Molecular Weight
48359.86 Da
References
  1. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [PubMed:8935801]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation.
Gene Name
DRD3
Uniprot ID
P35462
Uniprot Name
D(3) dopamine receptor
Molecular Weight
44224.335 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation...
Gene Name
HTR2B
Uniprot ID
P41595
Uniprot Name
5-hydroxytryptamine receptor 2B
Molecular Weight
54297.41 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE: Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73. [PubMed:8935801]

Drug created on October 29, 2015 12:11 / Updated on November 02, 2018 08:49