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Details

Stereochemistry ACHIRAL
Molecular Formula C28H32F2N2O.2ClH
Molecular Weight 523.485
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of VANOXERINE HYDROCHLORIDE

SMILES

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

InChI

InChIKey=MIBSKSYCRFWIRU-UHFFFAOYSA-N
InChI=1S/C28H32F2N2O.2ClH/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;2*1H

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

Molecular Formula ClH
Molecular Weight 36.461
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 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
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
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
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
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
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
Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.
2003 Mar 1
Interaction of cis-(6-benzhydrylpiperidin-3-yl)benzylamine analogues with monoamine transporters: structure-activity relationship study of structurally constrained 3,6-disubstituted piperidine analogues of (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidin-4-ylmethyl]amine.
2003 May 22
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
Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity.
2003 Sep
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
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
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
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
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
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
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
Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson's disease: relationship to transporter-dependent uptake.
2004 May
Methylphenidate restores ventral tegmental area dopamine neuron activity in prenatal ethanol-exposed rats by augmenting dopamine neurotransmission.
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 Thu Jul 06 16:43:39 UTC 2023
Edited
by admin
on Thu Jul 06 16:43:39 UTC 2023
Record UNII
MWO1IP03EV
Record Status Validated (UNII)
Record Version
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Name Type Language
VANOXERINE HYDROCHLORIDE
Common Name English
PIPERAZINE, 1-(2-(BIS(4-FLUOROPHENYL)METHOXY)ETHYL)-4-(3-PHENYLPROPYL)-, DIHYDROCHLORIDE
Systematic Name English
Code System Code Type Description
CAS
67469-78-7
Created by admin on Thu Jul 06 16:43:39 UTC 2023 , Edited by admin on Thu Jul 06 16:43:39 UTC 2023
PRIMARY
PUBCHEM
104920
Created by admin on Thu Jul 06 16:43:39 UTC 2023 , Edited by admin on Thu Jul 06 16:43:39 UTC 2023
PRIMARY
CHEBI
64086
Created by admin on Thu Jul 06 16:43:39 UTC 2023 , Edited by admin on Thu Jul 06 16:43:39 UTC 2023
PRIMARY
DRUG BANK
DBSALT001866
Created by admin on Thu Jul 06 16:43:39 UTC 2023 , Edited by admin on Thu Jul 06 16:43:39 UTC 2023
PRIMARY
FDA UNII
MWO1IP03EV
Created by admin on Thu Jul 06 16:43:39 UTC 2023 , Edited by admin on Thu Jul 06 16:43:39 UTC 2023
PRIMARY
EPA CompTox
DTXSID1042570
Created by admin on Thu Jul 06 16:43:39 UTC 2023 , Edited by admin on Thu Jul 06 16:43:39 UTC 2023
PRIMARY
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