Cebranopadol hemicitrate

Alias: Cebranopadol;GRT6005 hemicitrate; GRT 6005 hemicitrate; GRT-6005 hemicitrate; Cebranopadol hemicitrate;GRT-6005; GRT 6005; GRT6005;

Cat No.:V3265 Purity: ≥98%

COA Product Data Instructions for use SDS

Cebranopadol hemicitrate Chemical Structure CAS No.: 863513-92-2
Product category: Others 2

This product is for research use only, not for human use. We do not sell to patients.

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Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

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Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Biological Data

Product Description

Cebranopadol hemicitrate, the hemicitrate salt of Cebranopadol (also known as GRT-6005), is a novel, first in class compound with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor. Cebranopadol is an analgesic nociceptin/orphanin FQ peptide (NOP) that exhibits high potency and efficacy in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. It is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction.

Biological Activity I Assay Protocols (From Reference)

ln Vitro

In vitro activity: Cebranopadol (also known as GRT-6005) is a novel, first in class compound with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor. Cebranopadol is an analgesic nociceptin/orphanin FQ peptide (NOP) that exhibits high potency and efficacy in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. It is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction.

Kinase Assay: Human MOP, DOP, KOP, and NOP receptor binding assays were run in microtiter plates (Costar 3632; Corning Life Sciences, Tewksbury, MA) with wheat germ agglutinin-coated scintillation proximity assay beads (GE Healthcare, Chalfont St. Giles, UK). Cell membrane preparations of Chinese hamster ovary K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM, lot-No. 307-065-A) or the human DOP receptor (Art.-No. RBHODM, lot-No. 423-553-B), and human embryonic kidney cell line 293 cells transfected with the human NOP receptor (Art.-No. RBHORLM, lot-No. 1956) or the human KOP receptor (Art.-No. 6110558, lot-No. 295-769-A) were purchased from PerkinElmer Life and Analytical Sciences (Boston, MA). [N-allyl-2,3-3H]naloxone and [tyrosyl-3,5-3H]deltorphin II (both purchased from PerkinElmer Life and Analytical Sciences), [3H]Ci-977, and [leucyl-3H]nociceptin (both purchased from GE Healthcare) were used as ligands for the MOP, DOP, KOP, and NOP receptor binding studies, respectively.

Cell Assay: To test the agonistic activity of cebranopadol on human recombinant MOP, DOP, or NOP receptor-expressing cell membranes from Chinese hamster ovary K1 cells, or KOP receptor-expressing cell membranes from human embryonic kidney cell line 293 cells, 10 µg of membrane proteins per assay was incubated with 0.4 nM [35S]GTPγS (GE Healthcare) and different concentrations of agonists in buffer containing 20 mM HEPES (pH 7.4), 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN3, and 10 µM guanosine diphosphate for 45 minutes at 25°C. The bound radioactivity was determined as previously described.

ln Vivo

Behavioral studies in pain models and pharmacokinetic evaluations were conducted in Sprague-Dawley rats (weight range 134−423 g; tail-flick model: Iffa Credo, Brussels, Belgium; bone cancer model: Harlan Laboratories, Indianapolis, IN; all other pain models and pharmacokinetics: Janvier Laboratories, Le Genest Saint Isle, France); male rats were used for most of the experiments, except for the tail-flick and bone cancer models, for which female Sprague-Dawley rats were used. Studies in side effect models were conducted in male Wistar rats (weight range 150−375 g; Dépré, Saint Doulchard, France). Rats were housed under standard conditions (room temperature 20−24°C, 12 hour light/dark cycle, relative air humidity 35−70%, 10−15 air changes per hour, air movement<0.2 m/s) with food and water available ad libitum in the home cage. Animals were used only once in all in vivo models, except for models of mononeuropathy, for which they were tested repeatedly with a washout period of at least 1 week between tests. Apart from the exceptions mentioned below, animal testing was performed in accordance with the recommendations and policies of the International Association for the Study of Pain and the German Animal Welfare Law. All study protocols were approved by the local government committee for animal research, which is advised by an independent ethics committee. Animals were assigned randomly to treatment groups. Different doses and vehicles were tested in a randomized fashion. Although the operators performing the behavioral tests were not formally ''''blinded'''' with respect to the treatment, they were not aware of the study hypothesis or the nature of differences between drugs.

Animal Protocol

8.9 and 26.6 mg/kg s.c. for whole-body plethysmography test in conscious rats.

Sprague-Dawley rats

References

J Pharmacol Exp Ther.2014 Jun;349(3):535-48;J Pharmacol Exp Ther.2017 Sep;362(3):378-384.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C54H62F2N4O9
Molecular Weight	949.088302135468
CAS #	863513-92-2
Related CAS #	863513-91-1 (free); 863513-93-3 ((1α,4α)stereoisomer)
SMILES	FC1C=CC2=C(C=1)C1CCOC3(C=1N2)CCC(C1C=CC=CC=1)(CC3)N(C)C.FC1C=CC2=C(C=1)C1CCOC3(C=1N2)CCC(C1C=CC=CC=1)(CC3)N(C)C.OC(C(=O)O)(CC(=O)O)CC(=O)O
Synonyms	Cebranopadol;GRT6005 hemicitrate; GRT 6005 hemicitrate; GRT-6005 hemicitrate; Cebranopadol hemicitrate;GRT-6005; GRT 6005; GRT6005;
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)

Solubility Data

Solubility (In Vitro)

DMSO: >10mM

Water:N/A

Ethanol:N/A

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
(e.g. IP/IV/IM/SC)

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)

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).

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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

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.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.0536 mL	5.2682 mL	10.5364 mL
	5 mM	0.2107 mL	1.0536 mL	2.1073 mL
	10 mM	0.1054 mL	0.5268 mL	1.0536 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.

Calculator

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
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Enter 5 in the Volume box and choose the correct unit (mL)
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The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

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The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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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.

Note： (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.

Biological Data

Cebranopadol hemicitrate

Duration of action of cebranopadol (12µg/kg) compared with fentanyl (9.4µg/kg) and morphine (1.9 mg/kg) after intravenous administration in the rat tail-flick test.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.

Cebranopadol hemicitrate

Analgesic effect of cebranopadol on spinal nerve ligation-induced mononeuropathic pain (SNL) and complete Freund’s adjuvant-induced chronic rheumatoid arthritic pain (CFA) 30 minutes after, and on tail flick-induced heat nociception (TF) 20 minutes after intravenous administration.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.

Effect of intravenous cebranopadol on mechanical sensitivity in the ipsilateral and contralateral paws in a rat model of bone cancer pain.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.

Cebranopadol hemicitrate

Antihyperalgesic activity of cebranopadol in streptozotocin (STZ)-treated and control rats measured as % MPE (mean ± S.E.M.;n= 10) by means of a paw pressure test in a model of STZ-induced diabetic polyneuropathy.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.

Cebranopadol hemicitrate

Effect of 1.0, 2.15, and 4.64 mg/kg i.p. J-113397 on the antihypersensitive effect of 1.7μg/kg i.v. cebranopadol (A) and 8.9 mg/kg i.v. morphine (B) in the spinal nerve ligation (SNL) model. Effect of 0.3 and 1.0 mg/kg i.p. naloxone on the antihypersensitive effect of 1.7μg/kg i.v. cebranopadol (C) and of 0.1, 0.3, and 1.0 mg/kg i.p.naloxone on the antihypersensitive effect of 8.9 mg/kg i.v. morphine (D) in the SNL model. Data are given as percentage of maximum possible effect (mean ± S.E.M.;n= 10) measured with an electronic von Frey filament based on the measurement of ipsilateral withdrawal thresholds 30 minutes after administration of cebranopadol or morphine.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.

Cebranopadol hemicitrate

Antiallodynic effect of repeated daily intraperitoneal administration of cebranopadol or vehicle as measured by number of paw lifts from a cold plate during 2 minutes (mean ± S.E.M.;n= 13–15) (A) or % MPE (B) in the chronic constriction injury model.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.

Dose-dependent effects of cebranopadol (A) and morphine (B) on motor coordination in rats.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.
Effects of cebranopadol (A and C) and morphine (B and D) on respiratory function in the whole-body plethysmography test in conscious rats.J Pharmacol Exp Ther.2014 Jun;349(3):535-48.