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Details

Stereochemistry ACHIRAL
Molecular Formula C28H32F2N2O
Molecular Weight 450.5633
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of VANOXERINE

SMILES

FC1=CC=C(C=C1)C(OCCN2CCN(CCCC3=CC=CC=C3)CC2)C4=CC=C(F)C=C4

InChI

InChIKey=NAUWTFJOPJWYOT-UHFFFAOYSA-N
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

HIDE SMILES / InChI

Molecular Formula C28H32F2N2O
Molecular Weight 450.5633
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Vanoxerine, also known as GBR-12909, is a piperazine derivative exhibiting potent selective inhibition of sodium-dependent dopamine reuptake transporters. Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Vanoxerine has also been observed as a potent blocker of the following channels: cardiac hERG/IKr potassium channel, Calcium channel, voltage-dependent, L type, alpha 1C subunit (also known as Cav1.2) and voltage-gated sodium channel Nav 1.5. Vanoxerine was studied as a potential treatment for atrial fibrillation. However, phase III clinical trials for this condition were terminated because of cardiac safety concerns. Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptors (nAChRs).

Originator

Curator's Comment: https://books.google.com/books?id=M5E_BAAAQBAJ&pg=PT171&dq=Drug+Discovery+for+the+Treatment+of+Addiction:+Medicinal+Chemistry+Strategies&hl=en&sa=X&ved=0ahUKEwjZjoCeuM_UAhVFVT4KHeFnAvwQ6AEIKDAA#v=onepage&q=VANOXERINE&f=false

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: Q12809|||Q9BUT7
Gene ID: 3757.0
Gene Symbol: KCNH2
Target Organism: Homo sapiens (Human)
9.3 nM [IC50]
Target ID: Q13936|||Q13922|||Q13930|||Q4VMI9
Gene ID: 775.0
Gene Symbol: CACNA1C
Target Organism: Homo sapiens (Human)
16.2 nM [IC50]
Target ID: Nicotinic acetylcholine receptor
2.32 µM [IC50]
0.7 nM [Ki]
Target ID: Q14524|||E9PFW7
Gene ID: 6331.0
Gene Symbol: SCN5A
Target Organism: Homo sapiens (Human)
34.6 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
400 mg single, oral (unknown)
Studied dose
Dose: 400 mg
Route: oral
Route: single
Dose: 400 mg
Sources:
unhealthy
n = 26
Health Status: unhealthy
Condition: atrial fibrillation
Sex: M+F
Food Status: UNKNOWN
Population Size: 26
Sources:
Disc. AE: Polymorphic ventricular tachycardia, torsades de pointe...
AEs leading to
discontinuation/dose reduction:
Polymorphic ventricular tachycardia (serious, 11.54%)
torsades de pointe (serious, 3.85%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Polymorphic ventricular tachycardia serious, 11.54%
Disc. AE
400 mg single, oral (unknown)
Studied dose
Dose: 400 mg
Route: oral
Route: single
Dose: 400 mg
Sources:
unhealthy
n = 26
Health Status: unhealthy
Condition: atrial fibrillation
Sex: M+F
Food Status: UNKNOWN
Population Size: 26
Sources:
torsades de pointe serious, 3.85%
Disc. AE
400 mg single, oral (unknown)
Studied dose
Dose: 400 mg
Route: oral
Route: single
Dose: 400 mg
Sources:
unhealthy
n = 26
Health Status: unhealthy
Condition: atrial fibrillation
Sex: M+F
Food Status: UNKNOWN
Population Size: 26
Sources:
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats.
2001 Aug 15
[3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel probes for the dopamine transporter.
2001 Dec 17
Uptake of the dopaminergic neurotoxin, norsalsolinol, into PC12 cells via dopamine transporter.
2001 Jun
Effects of repeated GBR 12909 administration on brain stimulation reward.
2001 May 11
Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior.
2001 Nov
Repeated cocaine administration into the rat ventral tegmental area produces behavioral sensitization to a systemic cocaine challenge.
2001 Nov 29
The dopamine transporter in mesencephalic cultures is refractory to physiological changes in membrane voltage.
2001 Oct 1
Locomotor activity induced by noncompetitive NMDA receptor antagonists versus dopamine transporter inhibitors: opposite strain differences in inbred long-sleep and short-sleep mice.
2002 Apr
New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain.
2002 Dec 15
Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys.
2002 Jan
Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys.
2002 Jul
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.
2002 Jul
Preclinical evaluation of GBR12909 decanoate as a long-acting medication for methamphetamine dependence.
2002 Jun
Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine ('ecstasy')-induced dopamine release and free radical formation in the mouse striatum.
2002 Jun
Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.
2002 Jun-Aug
Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation.
2002 Mar-Apr
Characterization of nicotinic agonist-induced [(3)H]dopamine release from synaptosomes prepared from four mouse brain regions.
2002 May
GBR-12909 effect on dopamine outflow depends on phosphorylation in the caudate nucleus of the rat.
2002 Nov
Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens.
2002 Oct
Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease.
2002 Oct
Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors.
2002 Sep 1
Piperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909): high affinity ligands for the dopamine transporter.
2002 Sep 12
Dopamine reuptake inhibition and failure to evoke dyskinesia in MPTP-treated primates.
2002 Sep 13
Inhibition of vesicular uptake of monoamines by hyperforin.
2002 Sep 27
Further exploration of 1-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]piperazine (GBR 12909): role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter.
2003 Apr 7
Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture.
2003 Aug
Synthesis and dopamine transporter affinity of chiral 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(2-hydroxypropyl)piperazines as potential cocaine abuse therapeutic agents.
2003 Feb 10
1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum.
2003 Jan
Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.
2003 Mar 1
Dopamine transporter as target for drug development of cocaine dependence medications.
2003 Oct 31
Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter.
2003 Sep 1
Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats.
2004
Agents in development for the management of cocaine abuse.
2004
Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists.
2004
Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain.
2004
An animal model with relevance to schizophrenia: sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development.
2004
In vivo evidence that genetic background controls impulse-dependent dopamine release induced by amphetamine in the nucleus accumbens.
2004 Apr
Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS.
2004 Aug 23
Characterization of dopamine transport in crude synaptosomes prepared from rat medial prefrontal cortex.
2004 Aug 30
Effects of iptakalim on rotenone-induced cytotoxicity and dopamine release from PC12 cells.
2004 Aug 5
Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia.
2004 Feb
Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice.
2004 Jul
Cocaine-like discriminative stimulus effects of heroin: modulation by selective monoamine transport inhibitors.
2004 Jul
Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909 in mice.
2004 Jul
Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol [(+)-PD 128,907].
2004 Mar
Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson's disease: relationship to transporter-dependent uptake.
2004 May
Drug discrimination in methamphetamine-trained monkeys: effects of monoamine transporter inhibitors.
2004 Nov
Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.
2004 Oct
Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).
2004 Sep
Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys.
2004 Sep
Patents

Patents

Sample Use Guides

oral single doses of 100, 200 and 300 mg GBR 12909 (VANOXERINE) | 50, 100 and 150 mg GBR 12909 and placebo once daily for 7 days
Route of Administration: Oral
To compare Multiple Ion Channel Effects (MICE) effects, it was measured block of hERG, hCav 1.2 and hNav 1.5 channel currents using concentrations related to drug exposure levels: 0-10000 nM for vanoxerine. It was defined the concentration-responses (CRs) of vanoxerine for hERG (9 nM), hCav 1.2 (16 nM) and peak and late hNav 1.5 currents (35 nM and 85 nM, correspondingly).
Substance Class Chemical
Created
by admin
on Wed Jul 05 23:14:24 UTC 2023
Edited
by admin
on Wed Jul 05 23:14:24 UTC 2023
Record UNII
90X28IKH43
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
VANOXERINE
INN  
INN  
Official Name English
GBR 12909
Code English
1-(2-(BIS(P-FLUOROPHENYL)METHOXY)ETHYL)-4-(3-PHENYLPROPYL)PIPERAZINE
Common Name English
vanoxerine [INN]
Common Name English
GBR-12909
Code English
Classification Tree Code System Code
NCI_THESAURUS C66884
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
Code System Code Type Description
DRUG BANK
DB03701
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
FDA UNII
90X28IKH43
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
NCI_THESAURUS
C81084
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
PUBCHEM
3455
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
INN
6307
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
CAS
67469-69-6
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
MESH
C043425
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
EPA CompTox
DTXSID8045143
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
CHEBI
64089
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
ChEMBL
CHEMBL281594
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
EVMPD
SUB00023MIG
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
WIKIPEDIA
VANOXERINE
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
SMS_ID
100000079072
Created by admin on Wed Jul 05 23:14:24 UTC 2023 , Edited by admin on Wed Jul 05 23:14:24 UTC 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
Potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly frequency-dependent especially for Na and Ca channels;has characteristics of a potentially effective and safe antiarrhythmic.
IC50
METABOLIC ENZYME -> SUBSTRATE
MINOR
METABOLIC ENZYME -> SUBSTRATE
MAJOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
SALT/SOLVATE -> PARENT
BINDER->LIGAND
BINDING
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ACTIVE MOIETY