Dopamine reuptake (Ki = 1 nM)[1]

Vanoxerine (GBR-12909) is several times less effective as an inhibitor of norepinephrine and 5-HT uptake, and it inhibits dopamine (DA) uptake with an IC50 in the low nanomolar range [2]. Another oral mixed ion channel blocker with IKr, INa, and L-type calcium channel action is vanoxerine (GBR-12909) [3].

Vanoxerine (GBR-12909) (2.5-20 mg/kg; i.p.) greatly boosts the amount of walking that occurs [3].

The neurochemical profile of GBR 12909 (1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)pipera zine) was investigated. GBR 12909 was a potent and selective inhibitor of synaptosomal dopamine uptake (KI = 1 nM), with a 20-fold lower affinity for the histamine H1-receptor and a more than 100-fold affinity for the noradrenaline and 5-HT uptake carriers, the dopamine D-1, D-2, 5-HT2, 5-HT1A and alpha 1-receptors and voltage-dependent sodium channels. GBR 12909 (3 microM) was without effect on muscarinic, alpha 2, beta 1 + 2, gamma-aminobutyric acid (GABA) and benzodiazepine receptors, and on choline and GABA uptake carriers. The selective dopamine uptake inhibitory profile of GBR 12909 was confirmed by ex vivo uptake experiments. GBR 12909 inhibited uptake in vitro in a competitive manner as did cocaine and methylphenidate. [3H]GBR 12935 binding was competitively inhibited by GBR 12909 as well as by dopamine, cocaine and methylphenidate. Off-rate analysis of the [3H]GBR 12935 binding excluded the presence of allosteric binding sites on the dopamine carrier complex. Instead, the data favored the notion that GBR 12909 inhibits dopamine uptake by binding to the dopamine binding site on the carrier protein itself, thereby blocking the carrier process. In conclusion, GBR 12909 is a highly selective inhibitor of dopamine uptake, both in vivo and in vitro. At the moment GBR 12909 is the only compound with this neurochemical profile. The selective effect of GBR 12909 on this neuronal system makes it an interesting experimental tool and a potential antidepressant agent[2].

Animal/Disease Models: Male mice (6 weeks old ddY strain) [3]
Doses: 2.5, 5, 10, 20 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: The ambulation activity of mice increased in a dose-dependent manner. After administration Maximum increase is reached in 30 minutes.

Absorption, Distribution and Excretion
In healthy male volunteers (n=14), after oral administration of 25, 75, or 125 mg of vaproxil, the peak plasma concentrations (Cmax) were 17.9, 81.1, and 236.5 nmol/L, respectively, with corresponding areas under the curve (AUC) of 81, 365, and 1116 h·nmol/L. In the same group of subjects, the time to peak concentration (tmax) after oral administration of 25, 75, or 125 mg was 0.91, 0.93, and 1.13 h, respectively. The oral bioavailability of this drug depends on food intake. Compared with fasting individuals, volunteers who consumed low-fat and high-fat meals showed 76% and 255% higher bioavailability of vaproxil, respectively. Vaproxil is primarily excreted in urine, bile, and feces. Vaproxil can cross the blood-brain barrier and is distributed to multiple organs, including adipose tissue, lungs, liver, and gastrointestinal tract. Vanoxil has a large volume of distribution. The oral clearances of vanoxil at daily doses of 25, 75, and 125 mg are 660, 478, and 250 L/h, respectively. Metabolites/Metabolites: In vitro studies have shown that vanoxil is primarily metabolized by CYP3A4. CYP2C8 and CYP2E1 may also be involved in the metabolism of this drug. Selective inhibitors of CYP3A4 may interact with vanoxil. Known metabolites of vanoxil include 4-[3-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]piperazinyl]propyl]phenol and 1-phenyl-3-[4-[2-(4,4'-difluorophenylmethoxy)ethyl]piperazinyl]-1-propanol.

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Biological Half-Life
The mean elimination half-life of vanoxiline is 53.5 hours at 75 mg/day and 66 hours at 125 mg/day.

Protein Binding
Vanoxil showed 99% plasma protein binding at concentrations of 0.1, 0.4, and 1 μM.

[1]. Rothman RB, et al. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16.
[2]. Andersen PH. The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol.
[3]. Hirate K, et al. Characteristics of the ambulation-increasing effect of GBR-12909, a selective dopamine uptakeinhibitor, in mice. Jpn J Pharmacol. 1991 Apr;55(4):501-11.

Vanoxerine is an N-alkylpiperazine compound composed of a piperazine ring with 2-bis(4-fluorophenyl)methoxy[2-ethyl] and 3-phenylpropyl groups attached to positions 1 and 4, respectively. It is a potent competitive dopamine uptake inhibitor (Ki = 1 nM inhibition of striatal dopamine uptake). It has an affinity for norepinephrine and serotonin uptake carriers that is more than 100 times lower than that for dopamine. It is also a potent σ receptor ligand (IC50 = 48 nM). It exhibits central activity after systemic administration. It is a dopamine uptake inhibitor. It is an N-alkylpiperazine, organofluorine compound, tertiary amine compound, and ether compound. It is the conjugate base of vanoxerine(2+). Vanoxerine is a highly selective dopamine transporter antagonist. It was synthesized in the late 1970s and developed as a potential treatment for depression. Vanoxerine was later evaluated as a potential treatment for cocaine addiction because it blocks dopamine reuptake at a slower dissociation rate than cocaine. While some studies suggest that vanoxerine is safer than cocaine, others have found at least a moderate risk of abuse. Recently, vanoxerine has been tested as a potential antiarrhythmic and anti-atrial fibrillation drug because it blocks the hKV11.1 (hERG) cardiac potassium channel. Vanoxerine is an investigational drug and has not yet been approved for clinical use.

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Drug Indications
Vanoxerine has not yet been approved for clinical use.

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Mechanism of Action
Vanoxerine is a highly selective dopamine transporter antagonist. Because it inhibits dopamine reuptake, it has been thought that vanoxerine may be helpful in treating cocaine addiction. Cocaine increases dopamine levels in the synaptic cleft by binding to and blocking dopamine transporters. Compared to cocaine, varanoxiline has a higher affinity for the dopamine transporter, a slower dissociation rate, and does not possess the stimulant effects of cocaine. Varanoxiline is also used to treat conditions characterized by low dopamine levels, such as Parkinson's disease and depression. Varanoxiline is also a potent hKV11.1 (hERG) cardiac potassium channel blocker. Even at low concentrations, varanoxiline blocks calcium and sodium ion currents without significantly affecting the QT interval, action potential waveform, or transmural repolarization dispersion. Therefore, the antiarrhythmic and antifibrillation properties of varanoxiline have been investigated.

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Pharmacodynamics
Varanoxiline inhibits dopamine reuptake by binding to and blocking the dopamine transporter. The use of varanoxiline as a potential alternative to cocaine in the treatment of drug addiction has been evaluated. In primates, intravenous administration of vanoxerine reduced cocaine self-administration at a dose of 1 mg/kg and completely eliminated it at a dose of 3 mg/kg. No stimulant effects of cocaine were detected in healthy volunteers (n=8) treated with vanoxerine for two weeks, suggesting a lack of abuse potential. However, other studies have found that vanoxerine has at least moderate human abuse potential. The antiarrhythmic potential of vanoxerine has also been evaluated. A clinical study evaluating the efficacy of vanoxerine in converting atrial fibrillation (AF) or atrial flutter (AFL) to normal sinus rhythm reported that a significant proportion of patients with symptomatic AF/AFL who received 200, 300, and 400 mg of vanoxerine within 24 hours achieved sinus rhythm restoration. In studies evaluating doses ranging from 25 to 300 mg, vanoxerine was considered safe and well-tolerated.

C28H32F2N2O

334.71454

450.248

C, 74.64; H, 7.16; F, 8.43; N, 6.22; O, 3.55

67469-69-6

Vanoxerine dihydrochloride;67469-78-7

3455

Typically exists as solid at room temperature

1.135g/cm3

542.7ºC at 760 mmHg

282ºC

1.561

5.197

0

5

10

33

498

0

FC1=CC=C(C(C2=CC=C(F)C=C2)OCCN3CCN(CCCC4=CC=CC=C4)CC3)C=C1

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

1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine

GBR12,909; GBR-12909; Vanoxerine; 67469-69-6; Gbr 12909; Vanoxerine [INN]; ...; 67469-69-9 (free base); GBR12909; GBR 12909; I-893; I 893; I893.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)