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Identification
NameBicifadine
Accession NumberDB04889
TypeSmall Molecule
GroupsInvestigational
DescriptionBicifadine (DOV-220075) is a nonopioid analgesic. It is an inhibitor of both the norepinephrine and serotonin transporters and an NMDA antagonist with a non-narcotic profile. Bicifadine was shown to have potent analgesic activity in vivo and was chosen for further development for the treatment of pain.
Structure
Thumb
SynonymsNot Available
External Identifiers
  • DOV-220075
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Bicifadine hydrochloride
Thumb
  • InChI Key: OTZOPAFTLUOBOM-UHFFFAOYNA-N
  • Monoisotopic Mass: 209.097127224
  • Average Mass: 209.715
DBSALT000817
Categories
UNIIB0SV3N7J3H
CAS number71195-57-8
WeightAverage: 173.2542
Monoisotopic: 173.120449485
Chemical FormulaC12H15N
InChI KeyOFYVIGTWSQPCLF-UHFFFAOYSA-N
InChI
InChI=1S/C12H15N/c1-9-2-4-10(5-3-9)12-6-11(12)7-13-8-12/h2-5,11,13H,6-8H2,1H3
IUPAC Name
1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane
SMILES
CC1=CC=C(C=C1)C12CC1CNC2
Pharmacology
IndicationFor the treatment of pain.
Structured Indications Not Available
PharmacodynamicsBicifadine is a chemically distinct molecule with a unique profile of pharmacological activity. Its primary pharmacological action is to enhance and prolong the actions of norepinephrine and serotonin by inhibiting the transport proteins that terminate the physiological actions of the two biogenic amines. Bicifadine is not a narcotic and is well-tolerated and, in preclinical studies, has been shown not to act at any opiate receptor. Bicifadine does not exhibit any anti-inflammatory activity and does not inhibit prostaglandin synthetase in vitro.
Mechanism of actionPreclinical studies and clinical trials indicate that bicifadine's analgesic properties result through the enhancement and prolongation of norepinephrine and serotonin actions, however other actions may be involved.
TargetKindPharmacological actionActionsOrganismUniProt ID
Sodium-dependent noradrenaline transporterProteinunknownNot AvailableHumanP23975 details
Sodium-dependent serotonin transporterProteinunknownNot AvailableHumanP31645 details
D(2) dopamine receptorProteinunknownNot AvailableHumanP14416 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

The primary enzymes responsible for the primary metabolism of bicifadine in humans are MAO-B and CYP2D6.

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Basile AS, Janowsky A, Golembiowska K, Kowalska M, Tam E, Benveniste M, Popik P, Nikiforuk A, Krawczyk M, Nowak G, Krieter PA, Lippa AS, Skolnick P, Koustova E: Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. J Pharmacol Exp Ther. 2007 Jun;321(3):1208-25. Epub 2007 Feb 26. [PubMed:17325229 ]
  2. Erickson DA, Hollfelder S, Tenge J, Gohdes M, Burkhardt JJ, Krieter PA: In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human. Drug Metab Dispos. 2007 Dec;35(12):2232-41. Epub 2007 Sep 19. [PubMed:17881661 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9892
Caco-2 permeable+0.5488
P-glycoprotein substrateSubstrate0.6709
P-glycoprotein inhibitor INon-inhibitor0.9024
P-glycoprotein inhibitor IINon-inhibitor0.8295
Renal organic cation transporterInhibitor0.5272
CYP450 2C9 substrateNon-substrate0.8093
CYP450 2D6 substrateNon-substrate0.7758
CYP450 3A4 substrateNon-substrate0.6496
CYP450 1A2 substrateNon-inhibitor0.7326
CYP450 2C9 inhibitorNon-inhibitor0.8512
CYP450 2D6 inhibitorInhibitor0.6308
CYP450 2C19 inhibitorNon-inhibitor0.7716
CYP450 3A4 inhibitorInhibitor0.5
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5315
Ames testNon AMES toxic0.6881
CarcinogenicityNon-carcinogens0.8996
BiodegradationNot ready biodegradable0.9418
Rat acute toxicity2.7878 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8583
hERG inhibition (predictor II)Non-inhibitor0.6854
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.172 mg/mLALOGPS
logP1.93ALOGPS
logP2.06ChemAxon
logS-3ALOGPS
pKa (Strongest Basic)10.6ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area12.03 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity54.31 m3·mol-1ChemAxon
Polarizability20.7 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPiperidines
Sub ClassPhenylpiperidines
Direct ParentPhenylpiperidines
Alternative Parents
Substituents
  • Phenylpiperidine
  • 3-phenylpyrrolidine
  • Aralkylamine
  • Toluene
  • Benzenoid
  • Monocyclic benzene moiety
  • Pyrrolidine
  • Pyrrole
  • Azacycle
  • Secondary amine
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Norepinephrine:sodium symporter activity
Specific Function:
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:
SLC6A2
Uniprot ID:
P23975
Molecular Weight:
69331.42 Da
References
  1. Basile AS, Janowsky A, Golembiowska K, Kowalska M, Tam E, Benveniste M, Popik P, Nikiforuk A, Krawczyk M, Nowak G, Krieter PA, Lippa AS, Skolnick P, Koustova E: Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. J Pharmacol Exp Ther. 2007 Jun;321(3):1208-25. Epub 2007 Feb 26. [PubMed:17325229 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Serotonin:sodium symporter activity
Specific Function:
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin an...
Gene Name:
SLC6A4
Uniprot ID:
P31645
Molecular Weight:
70324.165 Da
References
  1. Basile AS, Janowsky A, Golembiowska K, Kowalska M, Tam E, Benveniste M, Popik P, Nikiforuk A, Krawczyk M, Nowak G, Krieter PA, Lippa AS, Skolnick P, Koustova E: Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. J Pharmacol Exp Ther. 2007 Jun;321(3):1208-25. Epub 2007 Feb 26. [PubMed:17325229 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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. Basile AS, Janowsky A, Golembiowska K, Kowalska M, Tam E, Benveniste M, Popik P, Nikiforuk A, Krawczyk M, Nowak G, Krieter PA, Lippa AS, Skolnick P, Koustova E: Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. J Pharmacol Exp Ther. 2007 Jun;321(3):1208-25. Epub 2007 Feb 26. [PubMed:17325229 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
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 antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. Erickson DA, Hollfelder S, Tenge J, Gohdes M, Burkhardt JJ, Krieter PA: In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human. Drug Metab Dispos. 2007 Dec;35(12):2232-41. Epub 2007 Sep 19. [PubMed:17881661 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Primary amine oxidase activity
Specific Function:
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOB preferentially degrades benzylamine and phenylethylamine.
Gene Name:
MAOB
Uniprot ID:
P27338
Molecular Weight:
58762.475 Da
References
  1. Erickson DA, Hollfelder S, Tenge J, Gohdes M, Burkhardt JJ, Krieter PA: In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human. Drug Metab Dispos. 2007 Dec;35(12):2232-41. Epub 2007 Sep 19. [PubMed:17881661 ]
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Drug created on October 21, 2007 10:10 / Updated on August 17, 2016 12:24