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Purity: ≥98%
GBR-12935 is a novel, potent and selective dopamine reuptake inhibitor. 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.
GBR 12935 is a novel, potent, and selective dopamine reuptake inhibitor belonging to the piperazine derivative class. This compound was originally developed in ³H-radiolabeled form to map the distribution of dopaminergic neurons in the brain by selectively labeling the dopamine transporter. The hydrochloride salt form (GBR 12935 dihydrochloride) has CAS number 67469-81-2, molecular formula C₂₈H₃₆Cl₂N₂O, and molecular weight 487.5. GBR 12935 is currently widely used in animal studies of Parkinson‘s disease and brain dopamine pathways.| Targets |
The primary target of GBR 12935 is the dopamine transporter (DAT), where it potently binds to inhibit dopamine reuptake. In rat striatal membranes, GBR 12935 exhibits a Kd of 5.5 nM for DAT; in COS-7 cells, the Kd is 1.08 nM. This compound also inhibits the norepinephrine transporter (NET) to some extent (Ki = 225 nM), but has negligible effects on the serotonin transporter (SERT) (Ki = 6.5 mM). Additionally, GBR 12935 specifically binds to human CYP2D6 (Kd = 42.2 nM, Ki = 2.3 μM), which represents a significant off-target site.
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| 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 after GBR 12935 (10 nM; 2 minutes) is given [2]. Extracellular dopamine levels are raised by GBR 12935 (100 μM; 60 min) in contrast to locally perfused artificial cerebrospinal fluid (ACSF) [2]. In nucleus accumbens homogenates, GBR 12935 (1-9 nM) dose-dependently decreases [3H]dopamine's active absorption [2]. The increase in extracellular dopamine levels caused by GBR 12935 was dramatically decreased to basal levels when 100 μM sulpiride or raclopride were co-infused with 100 μM GBR 12935 [2].
12 reduces viability in K‑Ras(G12C)-mutant cell lines (H1792, H358, Calu‑1, H23) but not in cell lines lacking this mutation (A549, H1299, H1437) (Fig. 4g). In vitro studies demonstrate that GBR 12935 increases extracellular dopamine levels by inhibiting DAT-mediated dopamine reuptake. In the nucleus accumbens, 10 nM GBR 12935 elevates extracellular dopamine levels to approximately 400% of basal within 2 minutes of application. This compound dose-dependently inhibits [³H]-dopamine uptake in rat striatal homogenates, with approximately 50% inhibition at 1 μM and 85% at 10 μM. In nucleus accumbens homogenates, 1-9 nM GBR 12935 dose-dependently inhibits active [³H]dopamine uptake. Furthermore, GBR 12935 exhibits high affinity for human CYP2D6 with no significant binding to other CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP3A4) at concentrations up to 100 μM. |
| ln Vivo |
GBR 12935 (1–32 mg/kg; repeated injection; 7 days) caused a larger increase in locomotor activity in C57BL/6J mice as compared to DBA/2J mice, and 10 mg/kg; injection; 7 days) produced a small number of mice allergic to the stereotypy brought on by repeated cocaine injections [3].
In vivo studies demonstrate that GBR 12935 dose-dependently increases locomotor activity in mice. In C57BL/6J and DBA/2J inbred mouse strains, intraperitoneal administration of GBR 12935 (10, 20, 40 mg/kg) significantly enhances locomotor activity compared to vehicle, with increases of approximately 180% and 220% at the 40 mg/kg dose, respectively. However, unlike cocaine, GBR 12935 does not induce stereotypy at any tested dose and fails to induce conditioned place preference in mice, suggesting lower abuse potential. In rats, microinjection of GBR 12935 (1 μg/μL, 0.5 μL) into the nucleus accumbens elevates extracellular dopamine levels by approximately 150%, an effect that can be antagonized by co-injection of dopamine D2 receptor antagonists. |
| Enzyme Assay |
CYP2D6 Binding Assay: Incubate human liver microsomes (enriched in CYP2D6) with [³H]-GBR 12935 (0.1-10 μM) and CYP2D6-selective substrates at 37°C for 60 minutes. Remove unbound ligand by ultracentrifugation, detect microsome-bound radioactivity by liquid scintillation counting, and calculate a Kd of 42.2 nM.
DAT Competition Binding Assay: Prepare rat striatal membranes, incubate with varying concentrations of GBR 12935 (0.01-100 μM) and [³H]-WIN 35,428 or [³H]-dopamine, detect radioactivity by filtration and liquid scintillation counting, and determine a Kd of 5.5 nM for DAT in rat striatum.
CYP Inhibition Assay: Incubate human liver microsomes with 0.1-100 μM GBR 12935 and CYP2D6-specific substrates at 37°C for 30 minutes, terminate by adding organic solvent, quantify metabolites by HPLC to assess enzyme inhibition, and determine a Ki of 2.3 μM.
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| Cell Assay |
Striatal Homogenate Dopamine Uptake Assay: Dissect rat striatum and homogenize in ice-cold buffer, centrifuge to obtain crude synaptosomal fraction. Incubate synaptosomes with 0.01-100 μM GBR 12935 and [³H]-dopamine for 15 minutes at 37°C, filter and detect radioactivity to determine uptake inhibition.
Nucleus Accumbens Homogenate [³H]Dopamine Uptake Assay: Incubate nucleus accumbens homogenate with 1-9 nM GBR 12935 and [³H]dopamine to inhibit active uptake in a dose-dependent manner.
CYP2D6 Enzyme Activity Assay: Incubate human liver microsomes with 0.1-100 μM GBR 12935 and CYP2D6-specific substrates at 37°C for 30 minutes, terminate by adding organic solvent, and quantify metabolites by HPLC to assess enzyme inhibition.
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| 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 on day eight did not induce stereotypy in mice pretreated with seven consecutive injections of 32 mg/kg cocaine or saline. Animal Models: Use adult male DBA/2J and C57BL/6J mice (22-30 g) for behavioral studies. Dosing Regimen: Dissolve the drug in saline and administer via intraperitoneal injection. Dose range is 1-40 mg/kg. For repeat injection studies, administer daily for 7 days. Behavioral Assessment: Measure locomotor activity (distance traveled) and stereotypy (repetitive grooming, sniffing) for 120 minutes using an automated activity monitoring system. In the rat nucleus accumbens microinjection model, anesthetize Sprague-Dawley rats and implant a cannula targeting the nucleus accumbens; measure extracellular dopamine levels by microdialysis and HPLC. Data Analysis: Compare locomotor activity, stereotypy, and dopamine levels between treatment and control groups. |
| ADME/Pharmacokinetics |
GBR 12935 is a synthetic small molecule compound with a molecular weight of 414.58 (free base) or 487.5 (dihydrochloride). This compound appears as a white powder, with a solubility of 20 mg/mL in water (with warming) and 25 mg/mL in DMSO. The LogP value is approximately 4.5, indicating high lipophilicity. Protein binding is high, primarily to CYP2D6. Plasma half-life data are not clearly reported in available literature; however, due to its mechanism as a dopamine reuptake inhibitor, it is presumed to cross the blood-brain barrier. Storage conditions: powder is stable for long-term storage at 4°C, sealed and protected from moisture; solutions are stable for 6 months at -80°C and 1 month at -20°C. GBR 12935 is for research use only and is not intended for clinical therapy.
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| Toxicity/Toxicokinetics |
Based on available data, GBR 12935 exhibits a favorable safety profile within experimental dose ranges. In vitro, GBR 12935 shows no significant cytotoxicity to human liver microsomes or rat striatal neurons at concentrations up to 50 μM. Unlike cocaine, GBR 12935 does not induce conditioned place preference in mice at doses up to 40 mg/kg, suggesting lower abuse potential. However, this compound has potential drug-drug interaction risks via CYP2D6 inhibition: binding to CYP2D6 (Ki = 2.3 μM) may reduce the metabolism of CYP2D6 substrates. This compound has no approved clinical indications and is primarily used for preclinical research in neuroscience.
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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. [4]. Darmani NA. Cocaine and selective monoamine uptake blockers (sertraline, nisoxetine, and GBR 12935) prevent the d-fenfluramine-induced head-twitch response in mice. Pharmacol Biochem Behav. 1998 May;60(1):83-90. |
| Additional Infomation |
1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine is an N-alkylpiperazine with a piperazine ring structured by 2-(diphenylmethoxy)ethyl and 3-phenylpropyl groups attached at positions 1 and 4, respectively. It is a potent and selective dopamine uptake inhibitor (KD = 5.5 nM in the rat striatal membrane). It is an N-alkylpiperazine, ether, and tertiary amine compound. It is the conjugate base of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dionium(2+).
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| Molecular Formula |
C28H34N2O.C4H4O4
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| Molecular Weight |
530.65452
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| Exact Mass |
414.267
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| Elemental Analysis |
C, 81.12; H, 8.27; N, 6.76; O, 3.86
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| CAS # |
76778-22-8
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| Related CAS # |
GBR 12935 dihydrochloride;67469-81-2; 76778-22-8; 1349767-56-1
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| PubChem CID |
3456
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.067g/cm3
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| Boiling Point |
540.6ºC at 760 mmHg
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| Flash Point |
143.9ºC
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| Index of Refraction |
1.576
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| LogP |
4.63
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
31
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| Complexity |
440
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(CCOC(C2=CC=CC=C2)C3=CC=CC=C3)CCN(CCCC4=CC=CC=C4)CC1
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| InChi Key |
RAQPOZGWANIDQT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H34N2O/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
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| Chemical Name |
1-(2-benzhydryloxyethyl)-4-(3-phenylpropyl)piperazine
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| Synonyms |
GBR-12935; 76778-22-8;
GBR 12935; GBR12935; 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine; 1-(2-(benzhydryloxy)ethyl)-4-(3-phenylpropyl)piperazine; 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; DTXSID2043743;
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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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8845 mL | 9.4224 mL | 18.8448 mL | |
| 5 mM | 0.3769 mL | 1.8845 mL | 3.7690 mL | |
| 10 mM | 0.1884 mL | 0.9422 mL | 1.8845 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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