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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
Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity.
2001 Apr 27
Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats.
2001 Aug 15
Uptake of the dopaminergic neurotoxin, norsalsolinol, into PC12 cells via dopamine transporter.
2001 Jun
Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells.
2001 May
Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.
2001 May
Effects of repeated GBR 12909 administration on brain stimulation reward.
2001 May 11
The role of dopamine in the locomotor stimulant effects and tolerance to these effects of caffeine.
2001 May-Jun
Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior.
2001 Nov
Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes.
2001 Sep
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
Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice.
2002 Dec
Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine receptor sites.
2002 Dec
New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain.
2002 Dec 15
The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to rats.
2002 Jan
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
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
Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats.
2002 Mar
Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: chiral hydroxyl-containing derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine.
2002 Mar 14
Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation.
2002 Mar-Apr
Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.
2002 May 17
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
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
1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3.
2003 Apr
Structure-activity relationship studies of highly selective inhibitors of the dopamine transporter: N-benzylpiperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.
2003 Apr 10
Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture.
2003 Aug
1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum.
2003 Jan
Self-biting induced by activation of L-type calcium channels in mice: dopaminergic influences.
2003 Jan-Feb
Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.
2003 Mar 1
Behavioral effects of rimcazole analogues alone and in combination with cocaine.
2003 May 9
Inhibitory effect of the DA uptake blocker GBR 12909 on sodium channels of hippocampal neurons.
2003 Oct 27
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
A novel modulatory mechanism of sodium currents: frequency-dependence without state-dependent binding.
2004
Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists.
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
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine.
2004 Feb
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
Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys.
2004 Jan
Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice.
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
Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging.
2004 Jun
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
Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine.
2004 May
Methylphenidate restores ventral tegmental area dopamine neuron activity in prenatal ethanol-exposed rats by augmenting dopamine neurotransmission.
2004 May
Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).
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 Fri Dec 15 15:45:49 GMT 2023
Edited
by admin
on Fri Dec 15 15:45:49 GMT 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 Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
Code System Code Type Description
DRUG BANK
DB03701
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
FDA UNII
90X28IKH43
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
NCI_THESAURUS
C81084
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
PUBCHEM
3455
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
INN
6307
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
CAS
67469-69-6
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
MESH
C043425
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
EPA CompTox
DTXSID8045143
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
CHEBI
64089
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
ChEMBL
CHEMBL281594
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
EVMPD
SUB00023MIG
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
WIKIPEDIA
VANOXERINE
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
SMS_ID
100000079072
Created by admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
BINDING
IC50
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
TARGET -> INHIBITOR
BINDING
IC50
BINDER->LIGAND
BINDING
Related Record Type Details
ACTIVE MOIETY