Details
Stereochemistry | ACHIRAL |
Molecular Formula | C28H32F2N2O |
Molecular Weight | 450.5643 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
c1ccc(cc1)CCCN2CCN(CC2)CCOC(c3ccc(cc3)F)c4ccc(cc4)F
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
Molecular Formula | C28H32F2N2O |
Molecular Weight | 450.5643 |
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).
CNS Activity
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11249581
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
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: Q12809|||Q9BUT7 Gene ID: 3757.0 Gene Symbol: KCNH2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666 |
9.3 nM [IC50] | ||
Target ID: Q13936|||Q13922|||Q13930|||Q4VMI9 Gene ID: 775.0 Gene Symbol: CACNA1C Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666 |
16.2 nM [IC50] | ||
Target ID: Nicotinic acetylcholine receptor Sources: https://www.ncbi.nlm.nih.gov/pubmed/17207584 |
2.32 µM [IC50] | ||
Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12213078 |
0.7 nM [Ki] | ||
Target ID: Q14524|||E9PFW7 Gene ID: 6331.0 Gene Symbol: SCN5A Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666 |
34.6 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse 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%) Sources: torsades de pointe (serious, 3.85%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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: |
PubMed
Title | Date | PubMed |
---|---|---|
Oxygenated analogues of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents. | 1999 Dec 2 |
|
Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593. | 2000 Jul |
|
Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior. | 2000 Nov |
|
Vanoxerine National Institute on Drug Abuse. | 2000 Oct |
|
Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909. | 2001 Apr |
|
Effect of acute ethanol on striatal dopamine neurotransmission in ambulatory rats. | 2001 Apr |
|
Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus. | 2001 Jul |
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Dopaminergic role in stimulant-induced wakefulness. | 2001 Mar 1 |
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A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule. | 2001 Mar 1 |
|
Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label. | 2001 Mar 9 |
|
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 |
|
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 |
|
Drug addiction. Part III. Pharmacotherapy of addiction. | 2001 Sep-Oct |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
|
Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists. | 2004 |
|
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 |
|
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 |
|
Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. | 2004 Jun |
|
Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. | 2004 Oct |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2150527
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666
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
Edited
Sat Jun 26 07:39:55 UTC 2021
by
admin
on
Sat Jun 26 07:39:55 UTC 2021
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Record UNII |
90X28IKH43
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Record Status |
Validated (UNII)
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Record Version |
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NCI_THESAURUS |
C66884
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DB03701
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90X28IKH43
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C81084
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3455
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6307
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67469-69-6
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C043425
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67469-69-6
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CHEMBL281594
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SUB00023MIG
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VANOXERINE
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METABOLIC ENZYME -> SUBSTRATE |
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METABOLIC ENZYME -> SUBSTRATE |
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METABOLIC ENZYME -> SUBSTRATE |
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SALT/SOLVATE -> PARENT |
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ACTIVE MOIETY |