NAV

Vanoxerine

Identification

Summary

Vanoxerine is an investigational dopamine transporter antagonist suggested to be beneficial in the treatment of cocaine addiction.

Generic Name
Vanoxerine
DrugBank Accession Number
DB03701
Background

Vanoxerine is a highly selective dopamine transporter antagonist. It was synthesized in the late 1970s and developed as a potential treatment for depression.1 Vanoxerine was later evaluated as a potential treatment for cocaine addiction due to its ability to block dopamine reuptake with a slower dissociation rate than cocaine.3 Although several studies have suggested that the profile of vanoxerine is safer than that of cocaine,1,2 other studies have found that vanoxerine has at least moderate potential to be abused by humans.9 More recently, vanoxerine was tested as a potential anti-arrhythmic and anti-atrial fibrillatory agent due to its ability to block the hKV11.1 (hERG) cardiac potassium channel.4 Vanoxerine is an investigational drug and has not been approved for therapeutic use.

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 450.574
Monoisotopic: 450.248269984
Chemical Formula
C28H32F2N2O
Synonyms
  • 1-(2-(bis(p-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine
  • vanoxerina
  • Vanoxerine
External IDs
  • GBR 12909
  • GBR-12909
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Pharmacology

Indication

Vanoxerine has not been approved for therapeutic use.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Vanoxerine inhibits dopamine reuptake by binding and blocking the dopamine transporter. The use of vanoxerine has been evaluated as a potential substitute of cocaine in the treatment of drug addiction.1 In primates, the intravenous administration of vanoxerine reduced cocaine self-administration at 1 mg/kg and eliminated it at 3 mg/kg.1 The stimulant profile of cocaine was not detected in healthy volunteers (n=8) receiving vanoxerine for 2 weeks, suggesting a lack of abuse potential of vanoxerine.1 However, other studies have found that vanoxerine has at least moderate potential to be abused by humans.9

The antiarrhythmic potential of vanoxerine has also been assessed. A clinical study evaluating the efficacy of vanoxerine on the conversion of atrial fibrillation (AF) or atrial flutter (AFL) to normal sinus rhythm reported that, within 24 hours, a significant proportion of symptomatic AF/AFL patients treated with 200, 300 and 400 mg of vanoxerine converted to sinus rhythm.7 In studies that evaluated doses ranging from 25 to 300 mg, vanoxerine was considered to be safe and tolerable.1,2

Mechanism of action

Vanoxerine is a highly selective dopamine transporter antagonist. Due to its ability to inhibit dopamine reuptake, it has been suggested that vanoxerine may be beneficial in treating cocaine addiction.1 Cocaine increases the amount of dopamine in the synapse by attaching and blocking the dopamine transporter. Compared to cocaine, vanoxerine has a higher affinity for the dopamine transporter and a slower dissociation rate, without the stimulant profile of cocaine.3 The use of vanoxerine to treat conditions characterized by low levels of dopamine, such as Parkinson's disease and depression, has also been investigated.2

Vanoxerine is also a potent blocker of the hKV11.1 (hERG) cardiac potassium channel.4 Even at low concentrations, vanoxerine is capable of blocking calcium and sodium currents without having a significant effect on QT interval, action potential waveforms and transmural dispersion of repolarization.4 Because of this, the anti-arrhythmic and anti-atrial fibrillatory properties of vanoxerine have been investigated.4,5,6

TargetActionsOrganism
ASodium-dependent dopamine transporter
antagonist
Humans
UHERG human cardiac K+ channel
blocker
Humans
Absorption

At doses of 25, 75 or 125 mg, vanoxerine had a corresponding Cmax of 17.9, 81.1 and 236.5 nmol/L and a corresponding AUC of 81, 365 and 1116 h⋅nmol/L when given orally to healthy male volunteers (n=14).8 In this same set of subjects, tmax was reached at 0.91, 0.93 and 1.13 h at oral doses of 25, 75 or 125 mg, respectively. The oral bioavailability of this drug depends on food intake. Compared with those fasting, the bioavailability of vanoxerine in volunteers taking a low-fat and a high-fat meal was 76% and 255% higher, respectively.8

Volume of distribution

Vanoxerine is capable of crossing the blood-brain barrier and distributing to several organs such as fat tissue, lungs, liver and the gastrointestinal tract.8 Vanoxerine has a large volume of distribution.8

Protein binding

The plasma protein binding of vanoxerine is 99% at 0.1, 0.4 and 1 μM.4

Metabolism

In vitro studies suggest that vanoxerine is mostly metabolized by CYP3A4. CYP2C8 and CYP2E1 may also contribute to the metabolism of this drug.4 CYP3A4 selective-inhibitors may interact with vanoxerine.4

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Route of elimination

The majority of vanoxerine is excreted in urine, bile and feces.10

Half-life

The mean elimination half-life of vanoxerine was 53.5 h at 75 mg/day and 66 h at 125 mg/day.8

Clearance

At 25, 75 and 125 mg/day, vanoxerine had a corresponding oral clearance of 660, 478 and 250 L/h.

Adverse Effects
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Toxicity

A study performed in monkeys self-administering vanoxerine suggests that the self-administration of this drug in humans may develop behaviorally toxic effects.9

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbametapirThe serum concentration of Vanoxerine can be increased when it is combined with Abametapir.
AmiodaroneThe metabolism of Vanoxerine can be decreased when combined with Amiodarone.
AmprenavirThe metabolism of Vanoxerine can be decreased when combined with Amprenavir.
ApalutamideThe serum concentration of Vanoxerine can be decreased when it is combined with Apalutamide.
AprepitantThe metabolism of Vanoxerine can be decreased when combined with Aprepitant.
Food Interactions
No interactions found.

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Product Ingredients
IngredientUNIICASInChI Key
Vanoxerine hydrochlorideMWO1IP03EV67469-78-7MIBSKSYCRFWIRU-UHFFFAOYSA-N

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Phenylpropylamines / Benzylethers / N-alkylpiperazines / Fluorobenzenes / Aralkylamines / Aryl fluorides / Trialkylamines / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds
show 2 more
Substituents
1,4-diazinane / Amine / Aralkylamine / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Benzylether / Dialkyl ether / Diphenylmethane
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, tertiary amino compound, ether, N-alkylpiperazine (CHEBI:64089)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
90X28IKH43
CAS number
67469-69-6
InChI Key
NAUWTFJOPJWYOT-UHFFFAOYSA-N
InChI
InChI=1S/C28H32F2N2O/c29-26-12-8-24(9-13-26)28(25-10-14-27(30)15-11-25)33-22-21-32-19-17-31(18-20-32)16-4-7-23-5-2-1-3-6-23/h1-3,5-6,8-15,28H,4,7,16-22H2
IUPAC Name
1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine
SMILES
FC1=CC=C(C=C1)C(OCCN1CCN(CCCC2=CC=CC=C2)CC1)C1=CC=C(F)C=C1

References

General References
  1. Preti A: Vanoxerine National Institute on Drug Abuse. Curr Opin Investig Drugs. 2000 Oct;1(2):241-51. [Article]
  2. Sogaard U, Michalow J, Butler B, Lund Laursen A, Ingersen SH, Skrumsager BK, Rafaelsen OJ: A tolerance study of single and multiple dosing of the selective dopamine uptake inhibitor GBR 12909 in healthy subjects. Int Clin Psychopharmacol. 1990 Oct;5(4):237-51. doi: 10.1097/00004850-199010000-00001. [Article]
  3. Rothman RB, Baumann MH, Prisinzano TE, Newman AH: Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16. doi: 10.1016/j.bcp.2007.08.007. Epub 2007 Aug 9. [Article]
  4. Lacerda AE, Kuryshev YA, Yan GX, Waldo AL, Brown AM: Vanoxerine: cellular mechanism of a new antiarrhythmic. J Cardiovasc Electrophysiol. 2010 Mar;21(3):301-10. doi: 10.1111/j.1540-8167.2009.01623.x. Epub 2009 Oct 8. [Article]
  5. Obejero-Paz CA, Bruening-Wright A, Kramer J, Hawryluk P, Tatalovic M, Dittrich HC, Brown AM: Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk. Sci Rep. 2015 Nov 30;5:17623. doi: 10.1038/srep17623. [Article]
  6. Hagiwara-Nagasawa M, Kambayashi R, Goto A, Nunoi Y, Izumi-Nakaseko H, Takei Y, Matsumoto A, Sugiyama A: Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs. Cardiovasc Toxicol. 2021 Mar;21(3):206-215. doi: 10.1007/s12012-020-09612-3. Epub 2020 Oct 19. [Article]
  7. Dittrich HC, Feld GK, Bahnson TD, Camm AJ, Golitsyn S, Katz A, Koontz JI, Kowey PR, Waldo AL, Brown AM: COR-ART: A multicenter, randomized, double-blind, placebo-controlled dose-ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flutter to normal sinus rhythm. Heart Rhythm. 2015 Jun;12(6):1105-12. doi: 10.1016/j.hrthm.2015.02.014. Epub 2015 Feb 12. [Article]
  8. Ingwersen SH, Snel S, Mant TG, Edwards D: Nonlinear multiple-dose pharmacokinetics of the dopamine reuptake inhibitor vanoxerine. J Pharm Sci. 1993 Nov;82(11):1164-6. doi: 10.1002/jps.2600821120. [Article]
  9. Stafford D, LeSage MG, Rice KC, Glowa JR: A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule. Drug Alcohol Depend. 2001 Mar 1;62(1):41-7. doi: 10.1016/s0376-8716(00)00158-7. [Article]
  10. Brown, AM., et al. (2016). Vanoxerine for self-administration for terminating acute episodes of cardiac arrhythmia in mammals (U.S. Patent No. 2016/0038482 A1). U.S. Patent and Trademark Office. [Link]
  11. Tocris: Vanoxerine SDS [Link]
PubChem Compound
3455
PubChem Substance
46504818
ChemSpider
3337
BindingDB
22165
ChEBI
64089
ChEMBL
CHEMBL281594
ZINC
ZINC000022034135
Therapeutic Targets Database
DCL001032
Wikipedia
Vanoxerine

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentAtrial Fibrillation or Flutter1
2CompletedTreatmentAtrial Flutter / Symptomatic, recurrent Atrial Fibrillation1
1TerminatedTreatmentCocaine Abuse / Cocaine Related Disorders1
1Unknown StatusTreatmentCocaine Related Disorders3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<5 mMSDS
logP5.6Ingwersen SH, et al. Nonlinear multiple-dose pharmacokinetics of the dopamine reuptake inhibitor vanoxerine. J Pharm Sci. 1993 Nov;82(11):1164-6.
Predicted Properties
PropertyValueSource
Water Solubility0.00139 mg/mLALOGPS
logP4.9ALOGPS
logP6.24Chemaxon
logS-5.5ALOGPS
pKa (Strongest Basic)8.58Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area15.71 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity130.38 m3·mol-1Chemaxon
Polarizability49.93 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8735
Blood Brain Barrier+0.8614
Caco-2 permeable+0.5075
P-glycoprotein substrateNon-substrate0.7857
P-glycoprotein inhibitor INon-inhibitor0.7627
P-glycoprotein inhibitor IINon-inhibitor0.9403
Renal organic cation transporterNon-inhibitor0.6987
CYP450 2C9 substrateNon-substrate0.7336
CYP450 2D6 substrateNon-substrate0.8289
CYP450 3A4 substrateSubstrate0.5078
CYP450 1A2 substrateInhibitor0.8849
CYP450 2C9 inhibitorNon-inhibitor0.5778
CYP450 2D6 inhibitorNon-inhibitor0.8997
CYP450 2C19 inhibitorInhibitor0.6866
CYP450 3A4 inhibitorInhibitor0.5496
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6695
Ames testAMES toxic0.7917
CarcinogenicityCarcinogens 0.5931
BiodegradationNot ready biodegradable0.9967
Rat acute toxicity2.7191 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.643
hERG inhibition (predictor II)Non-inhibitor0.8415
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 MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0030900000-5e8f7c15341ae2c1a706
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-1040900000-14d6897a577acfe12d2e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0392700000-b5e59fd489c507daa2ff
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00kb-2290600000-3829a040620cd38b0c96
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0uec-2950100000-fa6b0f8cc48997df2251
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fxt-0790100000-41da45b66b61f949ea8b
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-203.6415
predicted
DeepCCS 1.0 (2019)
[M+H]+205.99951
predicted
DeepCCS 1.0 (2019)
[M+Na]+212.7501
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Details1. Sodium-dependent dopamine transporter
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Monoamine transmembrane transporter activity
Specific Function
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A3
Uniprot ID
Q01959
Uniprot Name
Sodium-dependent dopamine transporter
Molecular Weight
68494.255 Da
References
  1. Preti A: Vanoxerine National Institute on Drug Abuse. Curr Opin Investig Drugs. 2000 Oct;1(2):241-51. [Article]
  2. Stepanov V, Jarv J: Kinetic mechanism of dopamine transporter interaction with 1-(2-(bis-(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909). Neurochem Int. 2008 Dec;53(6-8):370-3. doi: 10.1016/j.neuint.2008.09.005. Epub 2008 Sep 18. [Article]
Details2. HERG human cardiac K+ channel (Protein Group)
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Blocker
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Components:
NameUniProt ID
Potassium voltage-gated channel subfamily H member 2Q12809
Potassium voltage-gated channel subfamily H member 6Q9H252
Potassium voltage-gated channel subfamily H member 7Q9NS40
References
  1. Lacerda AE, Kuryshev YA, Yan GX, Waldo AL, Brown AM: Vanoxerine: cellular mechanism of a new antiarrhythmic. J Cardiovasc Electrophysiol. 2010 Mar;21(3):301-10. doi: 10.1111/j.1540-8167.2009.01623.x. Epub 2009 Oct 8. [Article]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
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. Cherstniakova SA, Bi D, Fuller DR, Mojsiak JZ, Collins JM, Cantilena LR: Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes. Drug Metab Dispos. 2001 Sep;29(9):1216-20. [Article]

Drug created at June 13, 2005 13:24 / Updated at May 21, 2022 03:10