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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
A comparison of the patterns of striatal Fos-like immunoreactivity induced by various dopamine agonists in rats.
2000 Aug 4
Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593.
2000 Jul
Vanoxerine National Institute on Drug Abuse.
2000 Oct
Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA ('ecstasy') on the 5-HT and dopamine concentrations in mouse brain.
2001
Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.
2001 Apr
Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity.
2001 Apr 27
Negative interaction of dopamine D2 receptor antagonists and GBR 12909 and GBR 12935 dopamine uptake inhibitors in the nucleus accumbens.
2001 Feb 23
Uptake of the dopaminergic neurotoxin, norsalsolinol, into PC12 cells via dopamine transporter.
2001 Jun
A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule.
2001 Mar 1
Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells.
2001 May
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
Repeated cocaine administration into the rat ventral tegmental area produces behavioral sensitization to a systemic cocaine challenge.
2001 Nov 29
Synthesis and biological evaluation of tropane-like 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) analogues.
2001 Nov 8
Behavioral responses to dopamine agonists in adult rats exposed to cocaine during the preweaning period.
2001 Sep
Mechanisms of MPP(+) incorporation into cerebellar granule cells.
2001 Sep 15
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
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.
2002 Jul
Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.
2002 Jun-Aug
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
Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease.
2002 Oct
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
Inhibition of vesicular uptake of monoamines by hyperforin.
2002 Sep 27
Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.
2003
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
S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats.
2003 Jan
Self-biting induced by activation of L-type calcium channels in mice: dopaminergic influences.
2003 Jan-Feb
Behavioral effects of rimcazole analogues alone and in combination with cocaine.
2003 May 9
Dopamine transporter as target for drug development of cocaine dependence medications.
2003 Oct 31
Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity.
2003 Sep
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
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
Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS.
2004 Aug 23
Effects of iptakalim on rotenone-induced cytotoxicity and dopamine release from PC12 cells.
2004 Aug 5
Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex.
2004 Feb
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
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