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
- 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
Pharmacology
- Indication
Vanoxerine has not been approved for therapeutic use.
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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
Target Actions Organism ASodium-dependent dopamine transporter antagonistHumans UHERG human cardiac K+ channel blockerHumans - 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Vanoxerine can be increased when it is combined with Abametapir. Amiodarone The metabolism of Vanoxerine can be decreased when combined with Amiodarone. Amprenavir The metabolism of Vanoxerine can be decreased when combined with Amprenavir. Apalutamide The serum concentration of Vanoxerine can be decreased when it is combined with Apalutamide. Aprepitant The metabolism of Vanoxerine can be decreased when combined with Aprepitant. - Food Interactions
- No interactions found.
Products
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- Product Ingredients
Ingredient UNII CAS InChI Key Vanoxerine hydrochloride MWO1IP03EV 67469-78-7 MIBSKSYCRFWIRU-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
- Preti A: Vanoxerine National Institute on Drug Abuse. Curr Opin Investig Drugs. 2000 Oct;1(2):241-51. [Article]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Tocris: Vanoxerine SDS [Link]
- External Links
- 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);">
Phase Status Purpose Conditions Count 3 Terminated Treatment Atrial Fibrillation or Flutter 1 2 Completed Treatment Atrial Flutter / Symptomatic, recurrent Atrial Fibrillation 1 1 Terminated Treatment Cocaine Abuse / Cocaine Related Disorders 1 1 Unknown Status Treatment Cocaine Related Disorders 3
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility <5 mM SDS logP 5.6 Ingwersen SH, et al. Nonlinear multiple-dose pharmacokinetics of the dopamine reuptake inhibitor vanoxerine. J Pharm Sci. 1993 Nov;82(11):1164-6. - Predicted Properties
Property Value Source Water Solubility 0.00139 mg/mL ALOGPS logP 4.9 ALOGPS logP 6.24 Chemaxon logS -5.5 ALOGPS pKa (Strongest Basic) 8.58 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 15.71 Å2 Chemaxon Rotatable Bond Count 10 Chemaxon Refractivity 130.38 m3·mol-1 Chemaxon Polarizability 49.93 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.8735 Blood Brain Barrier + 0.8614 Caco-2 permeable + 0.5075 P-glycoprotein substrate Non-substrate 0.7857 P-glycoprotein inhibitor I Non-inhibitor 0.7627 P-glycoprotein inhibitor II Non-inhibitor 0.9403 Renal organic cation transporter Non-inhibitor 0.6987 CYP450 2C9 substrate Non-substrate 0.7336 CYP450 2D6 substrate Non-substrate 0.8289 CYP450 3A4 substrate Substrate 0.5078 CYP450 1A2 substrate Inhibitor 0.8849 CYP450 2C9 inhibitor Non-inhibitor 0.5778 CYP450 2D6 inhibitor Non-inhibitor 0.8997 CYP450 2C19 inhibitor Inhibitor 0.6866 CYP450 3A4 inhibitor Inhibitor 0.5496 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6695 Ames test AMES toxic 0.7917 Carcinogenicity Carcinogens 0.5931 Biodegradation Not ready biodegradable 0.9967 Rat acute toxicity 2.7191 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.643 hERG inhibition (predictor II) Non-inhibitor 0.8415
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0udi-0030900000-5e8f7c15341ae2c1a706 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-1040900000-14d6897a577acfe12d2e Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0udi-0392700000-b5e59fd489c507daa2ff Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-00kb-2290600000-3829a040620cd38b0c96 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0uec-2950100000-fa6b0f8cc48997df2251 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0fxt-0790100000-41da45b66b61f949ea8b Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 203.6415 predictedDeepCCS 1.0 (2019) [M+H]+ 205.99951 predictedDeepCCS 1.0 (2019) [M+Na]+ 212.7501 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- Preti A: Vanoxerine National Institute on Drug Abuse. Curr Opin Investig Drugs. 2000 Oct;1(2):241-51. [Article]
- 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]
- 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:
Name | UniProt ID |
---|---|
Potassium voltage-gated channel subfamily H member 2 | Q12809 |
Potassium voltage-gated channel subfamily H member 6 | Q9H252 |
Potassium voltage-gated channel subfamily H member 7 | Q9NS40 |
References
- 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
- 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
- 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