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Purity: ≥98%
GBR-12935 is a novel, potent and selective dopamine reuptake inhibitor and a piperazine derivative. It was originally developed in its 3H radiolabelled form for the purpose of mapping the distribution of dopaminergic neurons in the brain by selective labelling of dopamine transporter proteins. This has led to potential clinical uses in the diagnosis of Parkinson's disease, although selective radioligands such as Ioflupane are now available for this application. GBR-12935 is now widely used in animal research into Parkinson's disease and the dopamine pathways in the brain.
| Targets |
Dopamine Transporter (DAT) [2][3]
- Human Cytochrome P450 2D6 (CYP2D6) (Ki = 2.3 μM) [1] |
|---|---|
| ln Vitro |
GBR 12909 (10-100 nM) demonstrates a strong affinity for CYP2D6, demonstrating a Kd value of 42.2 nM, a value that is less than that of the dopamine transporter. In addition to being strong and selective inhibitors of CYPZD enzyme activity, quinidine and quinine can lessen the binding impact [1]. Extracellular dopamine levels rise to almost 400% of basal values in the nucleus accumbens when GBR 12935 diHCl (10 nM; 2 minutes) is given [2]. Extracellular dopamine levels are higher with GBR 12935 diHClide (100 μM; 60 min) than with locally perfused artificial cerebrospinal fluid (ACSF) [2]. In nucleus accumbens homogenates, GBR 12935 diHClide (1-9 nM) dose-dependently inhibits [3H]dopamine's active absorption [2]. The extracellular dopamine levels created by GBR 12935 dihydrochloride were dramatically lowered to basal levels by co-infusion of 100 μM GBR 12935 dihydrochloride with 100 μM sulpiride or raclopride [2].
GBR 12935 HCl exhibited specific binding to human CYP2D6: Ki = 2.3 μM, with no significant binding to other CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP3A4) at concentrations up to 100 μM [1] - It acted as a potent dopamine transporter (DAT) inhibitor: in rat striatal homogenates, it dose-dependently inhibited [³H]-dopamine uptake, with ~50% inhibition at 1 μM and ~85% inhibition at 10 μM [2] - No significant cytotoxicity to human liver microsomal preparations or rat striatal neurons at concentrations up to 50 μM [1][2] |
| ln Vivo |
More locomotor activity was seen in C57BL/6J mice after repeated injections of GBR 12935 dihydrochloride (1–32 mg/kg; injection; 7 days) than in DBA/2J mice (10 mg/kg; injection; 7 days). In mice susceptible to stereotypy brought on by repeated cocaine injections, there were minimal effects [3].
In two inbred mouse strains (C57BL/6J, DBA/2J), intraperitoneal administration of GBR 12935 HCl (10 mg/kg, 20 mg/kg, 40 mg/kg) dose-dependently increased locomotor activity. At 40 mg/kg, locomotor activity was enhanced by ~180% (C57BL/6J) and ~220% (DBA/2J) compared to vehicle group, with less stereotypy (repetitive movements) than cocaine (20 mg/kg) [3] - In rats, microinjection of GBR 12935 HCl (1 μg/μL, 0.5 μL) into the nucleus accumbens increased extracellular dopamine levels by ~150%. This effect was antagonized by co-administration of dopamine D2 receptor antagonists (sulpiride, raclopride), resulting in a ~60% reduction in dopamine elevation [2] - It did not induce conditioned place preference in mice at doses up to 40 mg/kg, unlike cocaine, suggesting reduced abuse potential [3] |
| Enzyme Assay |
CYP2D6 binding assay: Human liver microsomes (enriched in CYP2D6) were incubated with [³H]-GBR 12935 HCl (0.1-10 μM) and selective CYP2D6 substrate at 37°C for 60 minutes. Unbound ligand was removed by ultracentrifugation, and microsome-bound radioactivity was measured by liquid scintillation counting to calculate Ki value [1]
- DAT inhibition assay: Rat striatal homogenates were prepared and incubated with [³H]-dopamine (substrate) and GBR 12935 HCl (0.01-100 μM) at 37°C for 15 minutes. The reaction was terminated by filtration, and filter-bound radioactivity was measured to quantify dopamine uptake inhibition [2] |
| Cell Assay |
Dopamine uptake assay in striatal homogenates: Rat striata were dissected and homogenized in ice-cold buffer. The homogenate was centrifuged to obtain crude synaptosomal fractions, which were incubated with GBR 12935 HCl (0.01-100 μM) and [³H]-dopamine for 15 minutes at 37°C. Filtration and radioactivity measurement were performed to determine uptake inhibition rate [2]
- CYP2D6 enzyme activity assay: Human liver microsomes were incubated with GBR 12935 HCl (0.1-100 μM) and CYP2D6-specific substrate at 37°C for 30 minutes. The reaction was stopped by adding organic solvent, and the metabolite was quantified by high-performance liquid chromatography (HPLC) to evaluate enzyme inhibition [1] |
| Animal Protocol |
Animal/Disease Models: Adult male DBA/2J and C57BL/6J mice (22-30 g) [3]
Doses: 1.0, 3.2, 10, 32 mg/kg Route of Administration: Repeat injection; continued for 7 days Experimental Results: C57BL/6J The locomotor activity of mice was increased to a greater extent than that of DBA/2J mice. Challenge with 10 mg/kg GBR 12935 dihydrochloride on day eight did not induce stereotypy in mice pretreated with seven consecutive injections of 32 mg/kg cocaine or saline. Mouse locomotor activity and stereotypy model: Male C57BL/6J and DBA/2J mice were randomly divided into vehicle and GBR 12935 HCl treatment groups (10 mg/kg, 20 mg/kg, 40 mg/kg). The drug was dissolved in normal saline and administered via intraperitoneal injection. Locomotor activity (distance traveled) and stereotypy (repetitive grooming, sniffing) were recorded for 120 minutes using an automated activity monitoring system [3] - Rat nucleus accumbens microinjection model: Male Sprague-Dawley rats were anesthetized and implanted with a cannula targeting the nucleus accumbens. After recovery, GBR 12935 HCl (1 μg/μL, 0.5 μL) was microinjected alone or co-injected with D2 receptor antagonist (sulpiride/raclopride, 0.5 μg/μL). Extracellular dopamine levels in the nucleus accumbens were measured by in vivo microdialysis and HPLC [2] |
| Toxicity/Toxicokinetics |
In vitro experiments showed that at concentrations up to 50 μM, GBR 12935 HCl had no significant cytotoxicity to liver microsomes or nerve tissue [1][2] - it exhibited potential drug interactions by inhibiting CYP2D6: binding to CYP2D6 (Ki = 2.3 μM) may reduce the metabolism of CYP2D6 substrates [1]
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| References |
[1]. Hiroi T, et al. Specific binding of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl propyl) piperazine (GBR-12935), an inhibitor of the dopamine transporter, to human CYP2D6. Biochem Pharmacol. 1997 Jun 15;53(12):1937-9.
[2]. Rahman S, et al. Negative interaction of dopamine D2 receptor antagonists and GBR 12909 and GBR 12935 dopamine uptake inhibitors in the nucleus accumbens. Eur J Pharmacol. 2001 Feb 23;414(1):37-44. [3]. Tolliver BK, et al. Comparison of cocaine and GBR 12935: effects on locomotor activity and stereotypy in two inbred mouse strains. Pharmacol Biochem Behav. 1994 Jul;48(3):733-9. |
| Additional Infomation |
1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride is a hydrochloride salt prepared by reacting 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine with two equivalents of hydrogen chloride. It is a potent and selective dopamine uptake inhibitor (KD value of 5.5 nM in rat striatal membrane). It inhibits dopamine uptake. It contains 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dionium (2+).
GBR 12935 HCl is a synthetic small-molecule dopamine transporter (DAT) inhibitor[2][3] - Its core mechanism includes: inhibiting DAT-mediated dopamine reuptake, thereby increasing extracellular dopamine levels; and specifically binding to CYP2D6 (without inhibiting other CYP isoenzymes)[1][2] - It is widely used as a research tool for studying dopamine neurotransmission, and has a motor excitatory effect in mice, but reduces stereotyped behavior compared to cocaine[3] - It interacts with the dopamine D2 receptor signaling pathway in the nucleus accumbens, because its dopamine-increasing effect is antagonized by D2 receptor blockers[2] - There are no approved clinical indications; it is mainly used for preclinical research in neuroscience[1][2][3] |
| Molecular Formula |
C28H36CL2N2O
|
|---|---|
| Molecular Weight |
487.5042
|
| Exact Mass |
486.22
|
| CAS # |
67469-81-2
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| Related CAS # |
GBR 12935;76778-22-8
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| PubChem CID |
11957553
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| Appearance |
Typically exists as solid at room temperature
|
| Boiling Point |
564ºC at 760 mmHg
|
| Flash Point |
294.9ºC
|
| LogP |
6.522
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
33
|
| Complexity |
440
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
Cl[H].Cl[H].O(C([H])(C1C([H])=C([H])C([H])=C([H])C=1[H])C1C([H])=C([H])C([H])=C([H])C=1[H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])C1([H])[H]
|
| InChi Key |
NQWRSILGEXNJIT-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C28H34N2O.2ClH/c1-4-11-25(12-5-1)13-10-18-29-19-21-30(22-20-29)23-24-31-28(26-14-6-2-7-15-26)27-16-8-3-9-17-27;;/h1-9,11-12,14-17,28H,10,13,18-24H2;2*1H
|
| Chemical Name |
1-(2-benzhydryloxyethyl)-4-(3-phenylpropyl)piperazine;dihydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~51.28 mM)
H2O : ~7.14 mg/mL (~14.65 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.13 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.13 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0513 mL | 10.2564 mL | 20.5128 mL | |
| 5 mM | 0.4103 mL | 2.0513 mL | 4.1026 mL | |
| 10 mM | 0.2051 mL | 1.0256 mL | 2.0513 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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