CCG 203769
目录号 : GC30875
CCG-203769是一种选择性的G蛋白信号调节因子(RGS4)抑制剂，CCG-203769阻断RGS4-Gαo蛋白-蛋白相互作用，IC50为17nM。
Cas No.:410074-60-1
Sample solution is provided at 25 µL, 10mM.
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CCG-203769 is a selective G protein signaling (RGS4) inhibitor, which blocks the RGS4-Gαo protein-protein interaction in vitro with an IC50 of 17 nM.
CCG-203769 also displays dramatic selectivity (8- to >5000-fold) for RGS4 over other RGS proteins. CCG-203769 inhibits RGS19 with an IC50 of 140 nM (8-fold selective for RGS4) and 6 μM for RGS16 (350-fold selective for RGS4). The closely related RGS8 is very weakly inhibited (IC50>60 μM) providing >4500-fold selectivity for RGS4. CCG-203769 inhibits GSK-3β with an IC50 value of 5 μM. CCG-203769 does not inhibit the cysteine protease papain at 100 μM. CCG-203769 does not inhibit RGS7, which lacks cysteines in the RGS domain. CCG-203769 inhibits RGS/Gαo binding in an RGS-selective manner. CCG-203769 enhances Gαq-dependent cellular Ca2+ signaling in an RGS4-dependent manner. CCG-203769 also blocks the GTPase accelerating protein (GAP) activity of RGS4. In single-turnover and steady-state GTPase experiments with Gαo and Gαi1, the rate of GTP hydrolysis is strongly stimulated by RGS4, and this effect is inhibited by CCG-203769 with an IC50<1 μM[1].
To determine whether this genetic disruption of RGS4 function can be replicated pharmacologically, CCG-203769 is tested for effects on Carbamoylcholine chloride-mediated bradycardia in conscious, unrestrained rats. Carbamoylcholine chloride (0.1 mg/kg, IP) produces a modest decrease in heart rate compared to that of a saline vehicle control. CCG-203769 (10 mg/kg, IV) has no significant effect upon heart rate when given alone. However, CCG-203769, administered immediately prior to Carbamoylcholine chloride, significantly potentiates the bradycardic effect (p < 0.05). Given the functional role of RGS4 in Parkinson's disease models, CCG-203769 is tested in a pharmacologic model of D2 antagonist-induced bradykinesia. Raclopride administration in rats causes increased hang time in the bar test, which is rapidly reversed by doses of CCG-203769 ranging from 0.1 to 10 mg/kg. The lowest dose, 0.01 mg/kg has no effect, while 0.1 mg/kg produces a submaximal effect. The higher doses, 1 and 10 mg/kg, produce equivalent effects. Similarly, the raclopride-induced paw drag in mice is reversed by 0.1-10 mg/kg CCG-203769[1].
[1]. Blazer LL, et al. Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS Chem Neurosci. 2015 Jun 17;6(6):911-9.
Kinase experiment: | Steady-state hydrolysis of unlabeled GTP is measured using malachite green in a receptor-independent assay utilizing a mutant Gαi1 (R178M, A326S). These mutations facilitate the release of GDP from the enzyme making the GTP hydrolysis step rate-limiting. GTP hydrolysis is measured by mixing 6 μM mutant Gαi with 300 μM GTP in 100 μL in 96-well plates in the presence or absence of 200 nM RGS4 and CCG-203769 or DMSO (vehicle control). All assay components are diluted in a buffer comprising 50 mM HEPES at pH 7.4, 100 mM NaCl, 0.01% Lubrol, 5 mM MgCl, and 10 μg/mL BSA. The reaction is allowed to proceed for 2 h at room temperature and then is quenched with 60 μL of an HCl/malachite green dye solution. Immediately after the addition of malachite green, 10 μL of 32% w/v sodium citrate is added as a colorimetric stabilizer, followed by incubation at room temperature for 20 min. Released inorganic phosphate is measured as an increase in absorbance (A630) from the complex of phosphate with malachite green. Background control samples lacking Gα are used to determine the rate of nonenzymatic GTP hydrolysis which is subtracted[1]. |
Animal experiment: | Mice[1]Young male (20-25 g; 8-9 weeks) C57BL/6J mice are used. Akinesia and bradykinesia are assessed 30 min after Raclopride, mice receive either DMSO or CCG-203769 (0.1-10 mg/kg, i.p.). Behavior is assessed 20 or 90 min after DMSO or CCG-203769. Rats[1]Adult Sprauge-Dawley rats receive CCG-203769 (10 mg/kg, i.v.) or saline (by i.v. infusion through the indwelling venous catheter over 30 s) while freely moving in their homecage. One minute later, saline or 0.1 mg/kg Carbamoylcholine chloride (i.p.) is administered. Before and after i.v. infusions, catheters are flushed with approximately 0.5 mL of heparinized saline (50 U/mL) to check catheter patency and flush treatments from the dead space in the catheter. |
References: [1]. Blazer LL, et al. Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS Chem Neurosci. 2015 Jun 17;6(6):911-9. | |
| Cas No. | 410074-60-1 | SDF | |
| Canonical SMILES | O=C(N1CCCC)N(CC)SC1=O | ||
| 分子式 | C8H14N2O2S | 分子量 | 202.27 |
| 溶解度 | DMSO : 62.5 mg/mL (308.99 mM) | 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 | 4.9439 mL | 24.7194 mL | 49.4389 mL |
| 5 mM | 0.9888 mL | 4.9439 mL | 9.8878 mL |
| 10 mM | 0.4944 mL | 2.4719 mL | 4.9439 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。
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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