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| Targets |
GRK2 Inhibitor specifically targets G protein-coupled receptor kinase 2 (GRK2), a member of the GRK family of serine/threonine kinases. GRK2 is primarily known for its role in homologous desensitization of GPCRs, particularly the β-adrenergic receptors. Upon agonist stimulation, GRK2 phosphorylates the activated receptor, creating a binding site for β-arrestin. β-arrestin binding sterically hinders G protein coupling and targets the receptor for internalization. Inhibition of GRK2 prevents this phosphorylation, thereby prolonging GPCR signaling. This is particularly relevant in heart failure, where GRK2 levels are elevated and contribute to reduced cardiac responsiveness to catecholamines.
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| ln Vitro |
In vitro, GRK2 Inhibitor is used to study the role of GRK2 in GPCR signaling pathways. By inhibiting GRK2 activity, the compound prevents the phosphorylation of GPCRs, which in turn prevents the binding of β-arrestin proteins to the receptors. This process, known as desensitization, is blocked, leading to enhanced and prolonged signaling through the receptor. The compound is typically used in cell-based assays to demonstrate that inhibition of GRK2 can restore or enhance signaling through various GPCRs, including β-adrenergic receptors. This helps to elucidate the role of GRK2 in receptor regulation and its contribution to disease states.
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| ln Vivo |
In vivo, GRK2 Inhibitor has been studied for its potential therapeutic effects in cardiovascular diseases. By inhibiting GRK2, the compound can enhance β-adrenergic receptor signaling, which is beneficial in conditions like heart failure where cardiac contractility is compromised. In animal models of heart failure, GRK2 inhibition has been shown to improve cardiac function, reduce remodeling, and increase survival. The compound is used to investigate the role of GRK2 in the pathophysiology of heart failure and to validate GRK2 as a therapeutic target for cardiovascular diseases.
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| Enzyme Assay |
Non-cellular in vitro assays for GRK2 Inhibitor involve kinase activity measurements. A typical protocol uses recombinant human GRK2 enzyme. The kinase reaction is performed in a buffer containing ATP, a peptide substrate (e.g., a peptide derived from the cytoplasmic tail of the β2-adrenergic receptor), and varying concentrations of the inhibitor. The reaction is initiated by the addition of the enzyme and incubated at 30°C for a specified time. The amount of phosphorylated substrate is then quantified using a luminescent or fluorescence-based detection method, such as the ADP-Glo™ Kinase Assay or by using radiolabeled [γ-³²P]ATP. The IC50 value is determined by plotting the percentage of kinase activity remaining against the log of the inhibitor concentration.
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| Cell Assay |
Cellular assays for GRK2 Inhibitor are performed using cell lines that endogenously or heterologously express GPCRs and GRK2, such as HEK293 or cardiomyocytes. Cells are treated with the inhibitor at various concentrations for a period of time (e.g., 1-4 hours). To assess GRK2 activity, cells are stimulated with a receptor agonist (e.g., isoproterenol for β-adrenergic receptors). Receptor phosphorylation is then assessed by immunoprecipitation of the receptor followed by Western blotting using phospho-specific antibodies. Alternatively, downstream signaling can be measured by assessing cAMP accumulation or ERK phosphorylation. The ability of the inhibitor to block receptor desensitization can be assessed by measuring receptor internalization using cell surface biotinylation or fluorescence microscopy.
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| Animal Protocol |
In vivo animal studies for GRK2 Inhibitor are commonly conducted in mouse or rat models of heart failure, such as the isoproterenol-induced cardiomyopathy model or the myocardial infarction model. Animals are administered the GRK2 Inhibitor via intraperitoneal (i.p.) or oral (p.o.) routes at doses such as 10-50 mg/kg. Treatment is typically given daily for 1-4 weeks. Cardiac function is assessed using echocardiography to measure parameters such as ejection fraction and fractional shortening. At the end of the study, heart tissues are harvested for histological analysis (e.g., fibrosis staining) and molecular analysis (e.g., GRK2 expression and activity, β-arrestin levels).
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| ADME/Pharmacokinetics |
GRK2 Inhibitor is a small molecule with a molecular weight of 263.2. It has a predicted density of 1.400 g/cm³. For in vivo studies, it is typically formulated in vehicles such as 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline, or similar aqueous solutions. The compound is light sensitive and should be stored under appropriate conditions. Detailed pharmacokinetic parameters, such as half-life, bioavailability, and clearance, have not been fully reported in the available literature. However, its use in animal models suggests that it has sufficient bioavailability to exert its effects.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for GRK2 Inhibitor have not been extensively reported. As a research chemical, it is not intended for human use and is strictly for preclinical research purposes. Standard safety precautions should be followed when handling this compound, including the use of personal protective equipment and working in a well-ventilated area. The compound is typically stored at -80°C for up to one year in solution. No specific toxicity data, such as LD50 values, are available in the provided literature.
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| References | |
| Additional Infomation |
GRK2 Inhibitor, also known as β-ARK1 Inhibitor, is a valuable pharmacological tool for studying the role of GRK2 in GPCR signaling and cardiovascular physiology. It is used to elucidate the mechanisms of receptor desensitization and to explore the therapeutic potential of GRK2 inhibition in heart failure. The compound is not a clinically approved drug and has not entered clinical trials. Its primary application is in academic and pharmaceutical research to validate GRK2 as a therapeutic target for cardiovascular diseases.
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| Molecular Formula |
C12H9NO6
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| Molecular Weight |
263.2
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| Exact Mass |
263.043
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| CAS # |
24269-96-3
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| PubChem CID |
5353430
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.261
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
19
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| Complexity |
377
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CC=C(/C=C/C2=CC=C([N+]([O-])=O)O2)O1)OC
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| InChi Key |
YDJPHSNZGRVPCK-NSCUHMNNSA-N
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| InChi Code |
InChI=1S/C12H9NO6/c1-17-12(14)10-6-4-8(18-10)2-3-9-5-7-11(19-9)13(15)16/h2-7H,1H3/b3-2+
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| Chemical Name |
methyl 5-[(E)-2-(5-nitrofuran-2-yl)ethenyl]furan-2-carboxylate
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| Synonyms |
βARK1 InhibitorGRK2 Inhibitor
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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) |
DMSO : ~41.67 mg/mL (~158.32 mM)
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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 | 3.7994 mL | 18.9970 mL | 37.9939 mL | |
| 5 mM | 0.7599 mL | 3.7994 mL | 7.5988 mL | |
| 10 mM | 0.3799 mL | 1.8997 mL | 3.7994 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04757571 | ACTIVE, NOT RECRUITING | Drug: Paroxetine Drug: Placebo |
Rheumatoid Arthritis | Sadat City University | 2021-02-01 | Phase 1 Phase 2 |
| NCT06203275 | NOT YET RECRUITING | Drug: Paroxetine Drug: Placebo |
Diabetes Mellitus, Type 2 | aya ramadan ashmawy sarhan | 2024-01 | Phase 3 |
| NCT05725837 | RECRUITING | Drug: Paroxetine | Sepsis Septic Shock |
Universidade do Extremo Sul Catarinense - Unidade Academica de Ciecias da Saude | 2023-06-10 | Phase 2 |
| NCT06231745 | RECRUITING | Drug: Methotrexate Drug: Paroxetine |
Rheumatoid Arthritis | Mostafa Bahaa | 2024-01-31 | Phase 3 |
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