Identification

Name
Fluspirilene
Accession Number
DB04842
Type
Small Molecule
Groups
Approved, Investigational
Description

A long-acting injectable antipsychotic agent used for chronic schizophrenia.

Structure
Thumb
Synonyms
  • Fluspirileno
  • Fluspirilenum
  • Imap
External IDs
Lopac-F-100 / MCN-JR-6218 / R 6218
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Imap Forte Inj 10mg/mlSuspension10 mgIntramuscularMcneil Pharmaceutical, Division Of Ortho Mcneil Inc.1982-12-311998-08-13Canada
Imap Inj 2mg/mlSuspension2 mgIntramuscularMcneil Pharmaceutical, Division Of Ortho Mcneil Inc.1977-12-311998-03-12Canada
International/Other Brands
Imap (Janssen) / lmap (McNeil) / Redeptin (SKF)
Categories
UNII
C5QA4GLR9M
CAS number
1841-19-6
Weight
Average: 475.5727
Monoisotopic: 475.243519039
Chemical Formula
C29H31F2N3O
InChI Key
QOYHHIBFXOOADH-UHFFFAOYSA-N
InChI
InChI=1S/C29H31F2N3O/c30-24-12-8-22(9-13-24)27(23-10-14-25(31)15-11-23)7-4-18-33-19-16-29(17-20-33)28(35)32-21-34(29)26-5-2-1-3-6-26/h1-3,5-6,8-15,27H,4,7,16-21H2,(H,32,35)
IUPAC Name
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
SMILES
FC1=CC=C(C=C1)C(CCCN1CCC2(CC1)N(CNC2=O)C1=CC=CC=C1)C1=CC=C(F)C=C1

Pharmacology

Indication

Used for the treatment of schizophrenia.

Pharmacodynamics

Fluspirilene is a relatively long-acting injectable depot antipsychotic drug used for schizophrenia. Fluspirilene does not differ greatly from other depot antipsychotics (fluphenazine decanoate, fluphenazine enathate, perphenazine onanthat, pipotiazine undecylenate) with respect to treatment efficacy, response or tolerability. Outcomes suggest that fluspirilene does not differ significantly from oral antipsychotics or in different weekly regimens, although much cannot be inferred because of the shortage of trials.

Mechanism of action
TargetActionsOrganism
AD(2) dopamine receptor
antagonist
Human
U5-hydroxytryptamine receptor 2A
antagonist
Human
UVoltage-dependent calcium channel gamma-1 subunit
inhibitor
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
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamineFluspirilene may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Fluspirilene.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Fluspirilene.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Fluspirilene.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Fluspirilene is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when 5-methoxy-N,N-dimethyltryptamine is combined with Fluspirilene.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Fluspirilene.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when Fluspirilene is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Fluspirilene.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Fluspirilene.
Food Interactions
  • Avoid alcohol.

References

Synthesis Reference

Janssen, P.A.J.; U.S. Patent 3,238,216; March 1, 1966; assigned to Research Laboratorium Dr. C. Janssen NV, Belgium.

US3238216
General References
Not Available
External Links
Human Metabolome Database
HMDB0015590
KEGG Drug
D02629
PubChem Compound
3396
PubChem Substance
46508202
ChemSpider
3279
BindingDB
26948
ChEBI
93369
ChEMBL
CHEMBL46516
Therapeutic Targets Database
DAP000980
PharmGKB
PA162565878
IUPHAR
85
Guide to Pharmacology
GtP Drug Page
Wikipedia
Fluspirilene
ATC Codes
N05AG01 — Fluspirilene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1
4Active Not RecruitingTreatmentSchizoaffective Disorders / Schizophrenia and Disorders With Psychotic Features / Schizophrenic Disorders1
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
SuspensionIntramuscular10 mg
SuspensionIntramuscular2 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)187.5-190Janssen, P.A.J.; U.S. Patent 3,238,216; March 1, 1966; assigned to Research Laboratorium Dr. C. Janssen NV, Belgium.
water solubility10 mg/L (at 25 °C)MERCK INDEX (1996)
logP5.86HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00167 mg/mLALOGPS
logP5.18ALOGPS
logP5.78ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)11.99ChemAxon
pKa (Strongest Basic)9.31ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area35.58 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity135.27 m3·mol-1ChemAxon
Polarizability50.88 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9807
Blood Brain Barrier+0.9713
Caco-2 permeable-0.68
P-glycoprotein substrateSubstrate0.7042
P-glycoprotein inhibitor IInhibitor0.9082
P-glycoprotein inhibitor IIInhibitor0.8257
Renal organic cation transporterInhibitor0.5978
CYP450 2C9 substrateNon-substrate0.835
CYP450 2D6 substrateNon-substrate0.5726
CYP450 3A4 substrateSubstrate0.645
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9209
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorInhibitor0.6989
CYP450 3A4 inhibitorInhibitor0.796
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7201
Ames testNon AMES toxic0.5428
CarcinogenicityNon-carcinogens0.8871
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6387 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8401
hERG inhibition (predictor II)Inhibitor0.9014
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-006t-9636300000-e318745a9958ecf316e7

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Phenylbutylamines / Phenylimidazolidines / Alpha amino acids and derivatives / Azaspirodecane derivatives / Dialkylarylamines / Aniline and substituted anilines / Fluorobenzenes / Aralkylamines / Imidazolidinones / Aryl fluorides
show 10 more
Substituents
Diphenylmethane / Phenylbutylamine / Phenylimidazolidine / Alpha-amino acid or derivatives / Azaspirodecane / Aniline or substituted anilines / Dialkylarylamine / Aralkylamine / Halobenzene / Fluorobenzene
show 26 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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed: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. [PubMed:17016423]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  4. Wang SJ: Inhibition of glutamate release by fluspirilene in cerebrocortical nerve terminals (synaptosomes). Synapse. 2002 Apr;44(1):36-41. [PubMed:11842444]
  5. 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
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
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only...
Gene Name
CACNG1
Uniprot ID
Q06432
Uniprot Name
Voltage-dependent calcium channel gamma-1 subunit
Molecular Weight
25028.105 Da
References
  1. Kenny BA, Fraser S, Kilpatrick AT, Spedding M: Selective antagonism of calcium channel activators by fluspirilene. Br J Pharmacol. 1990 Jun;100(2):211-6. [PubMed:1696149]
  2. Wang SJ: Inhibition of glutamate release by fluspirilene in cerebrocortical nerve terminals (synaptosomes). Synapse. 2002 Apr;44(1):36-41. [PubMed:11842444]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
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. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [PubMed:22039822]

Drug created on September 27, 2007 07:56 / Updated on August 26, 2018 02:00