CMPD101 |
| カタログ番号GC43286 |
CMPD101 は、それぞれ 18 nM および 5.4 nM の IC50 を持つ、強力で高度に選択的で膜透過性の GRK2/3 の低分子阻害剤です。
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 865608-11-3
Sample solution is provided at 25 µL, 10mM.
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CMPD101 is a potent, highly selective and membrane-permeable small-molecule inhibitor of G protein-coupled receptor kinase 2 (GRK2) and GRK3 (IC50s=18 and 5.4nM, respectively)[1]. GRKs phosphorylate GPCRs, regulate their desensitization, internalization, and signaling, are crucial for cellular and physiological regulation[2]. CMPD101 can be used for the research of GPCR desensitization and internalization, opioid tolerance, heart failure, signal transduction mechanisms, and drug development[3][4].
In vitro, treatment of HEK293 cells with CMPD101 (30µM; 30min) completely blocked histamine H1 receptor–mediated ERK1/2 phosphorylation (IC50=6µM)[5]. CMPD101 (3-30µM; 30min) inhibits the desensitization of µ-opioid receptors (MOPr) induced by agonists such as Met-Enk and DAMGO in locus coeruleus (LC) neurons of rats and mice, with an IC50 of approximately 6µM. In HEK293 cells, CMPD101 (30µM; 30min) almost completely inhibits [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin(DAMGO)-induced m-opioid receptor (MOPr) phosphorylation at Ser375, arrestin translocation, and MOPr internalization[6].
In vivo, pretreatment with CMPD101(0.3mg/kg, i.p.) 15min before the drinking session enhanced the effect of nalfurafine on reducing alcohol intake in mice by inhibiting GRK2/3 activity[7].
References:
[1] Okawa T, Aramaki Y, Yamamoto M, et al. Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure. J Med Chem. 2017;60(16):6942-6990.
[2] Mayor F Jr, Murga C. G Protein-Coupled Receptor Kinases Take Central Stage. Cells. 2022;12(1):23.
[3] Mann A, Keen AC, Mark H, et al. New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling. Sci Rep. 2021;11(1):8288.
[4] Thal DM, Yeow RY, Schoenau C, Huber J, Tesmer JJ. Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Mol Pharmacol. 2011;80(2):294-303.
[5] Michinaga S, Nagata A, Ogami R, Ogawa Y, Hishinuma S. Differential regulation of histamine H1 receptor-mediated ERK phosphorylation by Gq proteins and arrestins. Biochem Pharmacol. 2023;213:115595.
[6] Lowe JD, Sanderson HS, Cooke AE, et al. Role of G Protein-Coupled Receptor Kinases 2 and 3 in μ-Opioid Receptor Desensitization and Internalization. Mol Pharmacol. 2015;88(2):347-356.
[7] Zhou Y, Liang Y. Involvement of GRK2 in modulating nalfurafine-induced reduction of excessive alcohol drinking in mice. Neurosci Lett. 2021;760:136092.
| Cell experiment [1]: | |
Cell lines | Human embryonic kidney 293 cells |
Preparation Method | Human embryonic kidney 293 cells (HEK 293) cells stably overexpressing hemagglutinin (HA)-tagged rat MOPr (HAMOPr) were cultured at 37°C in 5% CO2 in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum, 10U/ml penicillin, 10mg/ml streptomycin, and 250mg/ml G418. Cells were seeded onto 60mm dishes and grown to 90% confluence, then subjected to serum starvation for 24 hours. HEK 293 cells were prelabeled with primary antibody for 1 hour at 4°C before incubation with CMPD101 (3 or 30µM) for 30 minutes at 37°C. Cells were then stimulated with [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin(DAMGO) (10mM) at 37°C to induce internalization. DAMGO-induced internalization of HAMOPr was assessed by enzyme-linked immunosorbent assay (ELISA) and by confocal microscopy imaging. |
Reaction Conditions | 3 or 30µM; 30min |
Applications | CMPD101 almost completely inhibits DAMGO-induced m-opioid receptor (MOPr) internalization. |
| Animal experiment [2]: | |
Animal models | C57BL/6J (B6) mice |
Preparation Method | Male adult C57BL/6J mice (8 weeks of age) were placed on a 12-hour reverse lightdark cycle (lights off at 7:00 am) and housed individually in ventilated cages with steel lids and filter tops and given ad libitum access to food and water. In this two-bottle free choice paradigm, mice had access to alcohol for 24 hours every other day for 3 weeks. Both the 15% alcohol solution and water tubes were provided starting at 3 hours after lights off. After 4, 8 and 24 hours of alcohol access, both the water and alcohol intakes were recorded. Following the 3-week chronic intermittent access (CIA) procedure, the mice had high alcohol intake and preference. The CIA mice were pretreated with CMPD101 (0 or 0.3mg/kg, i.p.) 15 min before the drinking session, followed by nalfurafine (0, 1, 3 or 10μg/kg; i.p.) 5min before a drinking session (n=7–8), and then alcohol and water intake values were recorded. |
Dosage form | 0 or 0.3 mg/kg, i.p.; 15min |
Applications | Pretreatment with CMPD101 enhanced the effect of nalfurafine on reducing alcohol intake in mice. |
References: | |
| Cas No. | 865608-11-3 | SDF | |
| Canonical SMILES | O=C(C1=CC=CC(NCC2=NN=C(C3=CC=NC=C3)N2C)=C1)NCC4=CC=CC=C4C(F)(F)F | ||
| Formula | C24H21F3N6O | M.Wt | 466.5 |
| 溶解度 | 10mg/mL in ethanol, 20mg/mL in DMSO, or in DMF | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.1436 mL | 10.7181 mL | 21.4362 mL |
| 5 mM | 428.7 μL | 2.1436 mL | 4.2872 mL |
| 10 mM | 214.4 μL | 1.0718 mL | 2.1436 mL |
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Quality Control & SDS
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- Purity: >98.50%
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Average Rating: 5 (Based on Reviews and 31 reference(s) in Google Scholar.)
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