CMPD101
目录号 : GC43286A GRK2 and GRK3 inhibitor
Cas No.:865608-11-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
CMPD101 is an inhibitor of G protein-coupled receptor kinase 2 (GRK2) and GRK3 (IC50s = 18 and 5.4 nM, respectively). [1] It is selective for GRK2 and GRK3 over GRK1, GRK5, GRK6, and GRK7 (IC50s = 3,100, 2,300, >30,000, and 25,000 nM, respectively), as well as Rho-associated kinase 2 (ROCK-2) and PKCα (IC50s = 1,400 and 8,100 nM, respectively). CMPD101 induces cAMP accumulation in HEK293 cells expressing human β2-adrenergic receptors (EC50 = 10 µM). In isolated human prostate strips, CMPD101 (50 µM) inhibits contractions induced by electrical field stimulation, norepinephrine, phenylephrine, endothelin-1 , and U-46619 . [2]
Reference:
[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. 60(16), 6942-6990 (2017).
[2]. Yu, Q., Gratzke, C., Wang, Y., et al. Inhibition of prostatic smooth muscle contraction by the inhibitor of G protein-coupled receptor kinase 2/3, CMPD101. Eur. J. Pharmacol. 831, 9-19 (2018).
| 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Inhibition of prostatic smooth muscle contraction by the inhibitor of G protein-coupled receptor kinase 2/3, CMPD101
Eur J Pharmacol 2018 Jul 15;831:9-19.PMID:29698717DOI:10.1016/j.ejphar.2018.04.022.
Alpha1-adrenoceptors induce prostate smooth muscle contraction, and hold a prominent role for pathophysiology and therapy of lower urinary tract symptoms in benign prostatic hyperplasia. G protein-coupled receptors are regulated by posttranslational regulation, including phosphorylation by G protein-coupled receptor kinases 2 and 3 (GRK2/3). Although posttranslational adrenoceptor regulation has been recently suggested to occur in the prostate, this is still marginally understood. With the newly developed CMPD101, a small molecule inhibitor with assumed specificity for GRK2/3 is now available. Here, we studied effects of CMPD101 on smooth muscle contraction of human prostate tissue. Electric field stimulation caused frequency-dependent contractions, which were inhibited concentration-dependently by CMPD101 (5 µM, 50 µM). 50 µM of CMPD101 did not affect myosin light chain (MCL) phosphorylation or Rho kinase activity, and did not alter contractions induced by highmolar KCl. Noradrenaline, the α1-adrenoceptor agonist phenylephrine, endothelin-1, and the thromboxane A2 analogue U46619 induced concentration-dependent contractions, which were inhibited by CMPD101 (50 µM). CMPD101 (50 µM) did not change phosphorylation of β2-adrenoceptors or β2-adrenergic relaxation of prostate strips. Molecular detection by Western blot and peroxidase staining suggested expression of GRK2 and GRK3 in human prostates. Double labeling in fluorescence staining confirmed that immunoreactivity for GRK2 and GRK3 was located to smooth muscle cells in the prostate stroma. In conclusion, CMPD101 inhibits adrenergic, neurogenic, and non-adrenergic smooth muscle contractions in the human prostate. Underlying mechanisms may be independent from GRK inhibition, and from inhibition of MLC kinase and Rho kinase. This may point to unknown properties of CMPD101.
Involvement of GRK2 in modulating nalfurafine-induced reduction of excessive alcohol drinking in mice
Neurosci Lett 2021 Aug 24;760:136092.PMID:34197905DOI:10.1016/j.neulet.2021.136092.
Though it is well known that G protein-coupled receptor kinase 2 [GRK2] is involved in regulation of mu opioid receptor [MOR] desensitization and morphine-related behaviors, the potential role of GRK2 in regulation of kappa opioid receptor [KOR] functions in vivo has not been established yet. A couple of recent studies have found that GRK2 activity desensitizes KOR functions via decreasing G protein-coupled signaling with sensitizing arrestin-coupled signaling. Nalfurafine, a G protein-biased KOR full agonist, produces an inhibitory effect on alcohol intake in mice, with fewer side effects (sedation, aversion, or anxiety/depression-like behaviors). Using RNA sequencing (RNA-seq) analysis, we first identified that nuclear transcript level of grk2 [adrbk1] (but not other grks) was significantly up-regulated in mouse nucleus accumbens shell (NAcs) after chronic excessive alcohol drinking, suggesting alcohol specifically increased NAcs grk2 expression. We then tested whether selective GRK2/3 inhibitor CMPD101 could alter alcohol intake and found that CMPD101 alone had no effect on alcohol drinking. Therefore, we hypothesized that the grk2 increase in the NAcs could modulate the nalfurafine effect on alcohol intake via interacting with the G protein-mediated KOR signaling. Nalfurafine decreased alcohol drinking in a dose-related manner, and pretreatment with CMPD101 enhanced the reduction in alcohol intake induced by nalfurafine, indicating an involvement of GRK2/3 blockade in modulating G protein-biased KOR agonism of nalfurafine. Together, our study provides initial evidence relevant to the transcriptional change of grk2 gene in the NAc shell after excessive alcohol drinking. Pharmacological GRK2/3 blockade enhanced nalfurafine's efficacy, suggesting a GRK2/3-mediated mechanism, probably through the G protein-mediated KOR signaling.
Role of G Protein-Coupled Receptor Kinases 2 and 3 in μ-Opioid Receptor Desensitization and Internalization
Mol Pharmacol 2015 Aug;88(2):347-56.PMID:26013542DOI:10.1124/mol.115.098293.
There is ongoing debate about the role of G protein-coupled receptor kinases (GRKs) in agonist-induced desensitization of the μ-opioid receptor (MOPr) in brain neurons. In the present paper, we have used a novel membrane-permeable, small-molecule inhibitor of GRK2 and GRK3, Takeda compound 101 (CMPD101; 3-[[[4-methyl-5-(4-pyridyl)-4H-1,2,4-triazole-3-yl] methyl] amino]-N-[2-(trifuoromethyl) benzyl] benzamidehydrochloride), to study the involvement of GRK2/3 in acute agonist-induced MOPr desensitization. We observed that CMPD101 inhibits the desensitization of the G protein-activated inwardly-rectifying potassium current evoked by receptor-saturating concentrations of methionine-enkephalin (Met-Enk), [d-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO), endomorphin-2, and morphine in rat and mouse locus coeruleus (LC) neurons. In LC neurons from GRK3 knockout mice, Met-Enk-induced desensitization was unaffected, implying a role for GRK2 in MOPr desensitization. Quantitative analysis of the loss of functional MOPrs following acute agonist exposure revealed that CMPD101 only partially reversed MOPr desensitization. Inhibition of extracellular signal-regulated kinase 1/2, protein kinase C, c-Jun N-terminal kinase, or GRK5 did not inhibit the Cmpd101-insensitive component of desensitization. In HEK 293 cells, CMPD101 produced almost complete inhibition of DAMGO-induced MOPr phosphorylation at Ser(375), arrestin translocation, and MOPr internalization. Our data demonstrate a role for GRK2 (and potentially also GRK3) in agonist-induced MOPr desensitization in the LC, but leave open the possibility that another, as yet unidentified, mechanism of desensitization also exists.
G protein-coupled receptor kinase-2 confers isoform-specific calcium sensitivity to dopamine D2 receptor desensitization
FASEB J 2021 Nov;35(11):e22013.PMID:34699610DOI:10.1096/fj.202100704RR.
The dopamine D2 receptor (D2 R) functions as an autoreceptor on dopaminergic cell bodies and terminals and as a postsynaptic receptor on a variety of neurons in the central nervous system. As a result of alternative splicing, the D2 R is expressed as two isoforms: long (D2L R) and short (D2S R) differing by a stretch of 29 residues in the third intracellular loop, with D2S R being the predominant presynaptic isoform. Recent reports described a Ca2+ sensitivity of the desensitization time course of potassium currents elicited via D2S R, but not via D2L R, when either isoform was selectively expressed in dopaminergic neurons. Here, we aimed to study the mechanism behind this subtype-specific Ca2+ sensitivity. Thus, we measured the desensitization of potassium channel responses evoked by D2L R and D2S R using two-electrode voltage clamp in Xenopus oocytes in the absence and presence of different amounts of β-arrestin2 and G protein-coupled receptor kinase-2 (GRK2), both of which are known to play important roles in D2 R desensitization in native cells. We found that co-expression of both GRK2 and β-arrestin2 was necessary for reconstitution of the Ca2+ sensitivity of D2S R desensitization, while D2L R did not display Ca2+ sensitivity under these conditions. The effect of Ca2+ chelation by BAPTA-AM to slow the rate of D2S R desensitization was mimicked by the GRK2 inhibitor, CMPD101, and by the kinase-inactivating GRK2 mutation, K220R, but not by the PKC inhibitor, Gö6976, nor by the calmodulin antagonist, KN-93. Thus, Ca2+ -sensitive desensitization of D2S R appears to be mediated via a GRK2 phosphorylation-dependent mechanism.
Apelin-Induced Relaxation of Coronary Arteries Is Impaired in a Model of Second-Hand Cigarette Smoke Exposure
J Cardiovasc Pharmacol 2022 Dec 1;80(6):842-851.PMID:PMC9729429DOI:10.1097/FJC.0000000000001354.
Apelin, an endogenous ligand for APJ receptors, causes nitric oxide (NO)-dependent relaxation of coronary arteries. Little is known about the effects of apelin/APJ receptor signaling in the coronary circulation under pathological conditions. Here, we tested the hypothesis that the vasorelaxing effect of apelin is impaired by cigarette smoke extract (CSE), an established model for second-hand smoke exposure. Isolated rat coronary arteries were treated with 2% CSE for 4 hours. Apelin-induced relaxation of coronary arteries was abolished by CSE exposure, while relaxations to acetylcholine (ACh) (endothelium-dependent relaxation) and to diethyl amine NONOate (NO donor) were similar in control and CSE-treated arteries. Immunoblot analysis demonstrated that apelin increased eNOS ser1177 phosphorylation under control conditions but had no effect after exposure to CSE. Moreover, GRK2 expression was increased in CSE-exposed coronary endothelial cells. Pretreatment with CMPD101, a GRK2 inhibitor, improved the relaxation response to apelin in CSE-exposed coronary arteries. CSE treatment failed to inhibit relaxations evoked by CMF-019, an APJ receptor biased agonist that has little effect on GRK2. In arteries exposed to CSE, apelin impaired the response to ACh but not to diethyl amine NONOate. ACh-induced relaxation was unaffected by CMF-019 in either control or CSE-treated coronary arteries. The results suggest that APJ receptor signaling using the GRK2 pathway contributes to both loss of relaxation to apelin itself and the ability of apelin to inhibit endothelium-dependent relaxation to ACh in CSE-exposed coronary arteries, likely because of impaired production of NO from endothelial cells. These changes in apelin/APJ receptor signaling under pathological conditions (eg, exposure to second-hand smoke) could create an environment that favors increased vasomotor tone in coronary arteries.