CMPD101
目录号 : GC43286CMPD101是一种高效、高选择性且具有膜通透性的小分子G蛋白偶联受体激酶2（GRK2）和GRK3抑制剂，其对GRK2和GRK3的IC50值分别为18nM和5.4nM。
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.
CMPD101是一种高效、高选择性且具有膜通透性的小分子G蛋白偶联受体激酶2（GRK2）和GRK3抑制剂，其对GRK2和GRK3的IC50值分别为18nM和5.4nM[1]。GRK通过磷酸化GPCR，调节其脱敏、内化和信号传导，在细胞和生理调节中发挥关键作用[2]。CMPD101可用于研究GPCR脱敏和内化、阿片类药物耐受性、心力衰竭、信号传导机制以及药物开发等领域[3][4]。
在体外实验中，用30µM的CMPD101处理HEK293细胞30分钟，可完全阻断组胺H1受体介导的ERK1/2磷酸化，IC50为6µM[5]。在大鼠和小鼠的蓝斑核（LC）神经元中，CMPD101（3-30µM；30分钟）可抑制由Met-Enk和DAMGO等激动剂诱导的μ-阿片受体（MOPr）脱敏，其IC50约为6µM。在HEK293细胞中，CMPD101（30µM；30分钟）几乎完全抑制[D-Ala2, N-MePhe4, Gly-ol5]-enkephalin（DAMGO）诱导的MOPr在Ser375位点的磷酸化、arrestin转位和MOPr内化[6]。
在体内实验中，小鼠在饮酒测试前15分钟腹腔注射CMPD101（0.3mg/kg）可通过抑制GRK2/3活性增强纳呋拉啡减少酒精摄入的效应[7]。
| 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 | |
| 化学名 | 3-[[[4-methyl-5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]methyl]amino]-N-[[2-(trifluoromethyl)phenyl]methyl]-benzamide | ||
| Canonical SMILES | O=C(C1=CC=CC(NCC2=NN=C(C3=CC=NC=C3)N2C)=C1)NCC4=CC=CC=C4C(F)(F)F | ||
| 分子式 | C24H21F3N6O | 分子量 | 466.5 |
| 溶解度 | 10mg/mL in ethanol, 20mg/mL in DMSO, or in DMF | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1436 mL | 10.7181 mL | 21.4362 mL |
| 5 mM | 0.4287 mL | 2.1436 mL | 4.2872 mL |
| 10 mM | 0.2144 mL | 1.0718 mL | 2.1436 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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2.
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