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H-89 dihydrochloride

CAS号

130964-39-5

分子式

C20H20BrN3O2S·2HCl

主要靶点

PKA|S6 Kinase|Autophagy

仅限科研使用

Cat No : CM01248

Print datasheet

Synonyms

Autophagy|H89|H-89|H-89 Dihydrochloride|H 89|H 89 2HCl|S6 Kinase|S6K1|S6Kinase|Protein kinase inhibitor H-89|Protein kinase inhibitor H-89 dihydrochloride|PKA

验证数据展示

  • CAS No.: 130964-39-5

    H-89 dihydrochloride
    CAS#: 130964-39-5

产品信息

CAS号 130964-39-5
分子式 C20H20BrN3O2S·2HCl
主要靶点 PKA|S6 Kinase|Autophagy
主要通路 PI3K/Akt/mTOR 信号通路|MAPK 信号通路|蛋白酪氨酸激酶|自噬
分子量 519.28
纯度 100%， 此纯度可做参考，具体纯度与批次有关系，可咨询客服
储存条件 Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice.
别名 Autophagy|H89|H-89|H-89 Dihydrochloride|H 89|H 89 2HCl|S6 Kinase|S6K1|S6Kinase|Protein kinase inhibitor H-89|Protein kinase inhibitor H-89 dihydrochloride|PKA

靶点活性

S6K1:80 nM (cell free)|PKA:48 nM (Ki, cell free)

体内活性

不同剂量的H-89（0.05、0.1、0.2 mg/100g）被腹腔内（i.p.）注射，于静脉注射PTZ（0.5% w/v）前30分钟施用。H-89（0.2 mg/100g）的腹腔注射显著延长了PTZ处理动物的发作潜伏期和阈值。用PTX（50和100 mg/kg）预处理动物，减弱了H-89（0.2 mg/100g）在PTZ暴露动物中的抗惊厥效果。H-89（0.05、0.2 mg/100g）阻止了bucladesine（300 nM）的癫痫发作活动，显著增加了发作潜伏期和发作阈值[4]。在OVA致敏/挑战的小鼠中，通过腹腔内（i.p.）注射H89（10 mg/kg）显著抑制了AHR，而对对照组小鼠的气道反应无影响。H89处理减少了嗜酸性粒细胞数量80%、中性粒细胞数量64%及淋巴细胞数量74%，对巨噬细胞无影响。在中度模型中，细胞浸润由39.3%嗜酸性粒细胞、58.5%巨噬细胞、1.9%中性粒细胞和0.3%淋巴细胞组成，且完全被H89抑制[5]。

体外活性

H-89对蛋白激酶A具有明显的选择性抑制作用，Ki值为0.048 microM。H-89预处理能够剂量依赖性抑制forskolin诱导的蛋白磷酸化，而对PC12D细胞内环磷腺苷(cyclic AMP)水平无降低作用，NGF诱导的蛋白磷酸化也未被抑制。H-89还显著抑制了PC12D细胞forskolin诱导的突起生长，即使在加入二丁酰环磷腺苷(dibutyryl cAMP)前添加H-89时亦可观察到此抑制效应。在细胞裂解液中，用H-89(30 microM)预处理PC12D细胞显著抑制了cAMP依赖的组蛋白IIb磷酸化活性，但对其他蛋白磷酸化活性无影响[1]。此外，H-89对S6K1、MSK1、ROCK-II、PKBα和MAPKAP-K1b的IC50值分别为0.08、0.12、0.27、2.6和2.8 μM[2]。在大鼠裸露的EDL纤维中，通过离子替代引起的去极化反应仅在10 microM H-89的作用下轻微受抑，该浓度远足以完全抑制PKA。在1-2 microM下，H-89显著减慢了大鼠裸露纤维的重新装填率。用100 microM H-89时，通过离子替代引起的去极化反应力完全被抑制。在小鼠屈指深肌(FDB)单一纤维中，1-3 microM H-89对动作电位介导的Ca2+瞬变无明显影响[3]。

溶解度

DMSO:60 mg/mL (115.54 mM);H2O:< 1 mg/mL (insoluble or slightly soluble);5% DMSO+95% Saline:3.16 mg/mL (6.09 mM)

细胞实验

After 48 h in culture, PCl2D cells are cultured in a test medium containing 30 μM H-89 for 1 h and then exposed to a fresh medium that contained both 10 μM forskolin and 30 μM H-89. Cells are scraped off with a rubber policeman and sonicated in the presence of 0.5 mL of 6% trichloroacetic acid. To extract trichloroacetic acid, 2 mL of petroleum ether is added, the preparation mixed and centrifuged at 3000 rpm for 10 min. After aspiration of the upper layer, the residue sample solution is used for determination [1].

动物实验

H89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide], di-HCl Salt) (10 mg/kg) suspended in 5% DMSO in saline was administered i.p. two hours before each OVA challenge (or two hours before the last OVA challenge). Control animals received equivalent volumes (200 μl) of 5% DMSO in saline [5].

参考文献

1.Chijiwa T, et al. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem. 1990 Mar 25;265(9):5267-72.
2.Davies SP, et al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
3.Blazev R, et al. Effects of the PKA inhibitor H-89 on excitation-contraction coupling in skinned and intact skeletal muscle fibres. J Muscle Res Cell Motil. 2001;22(3):277-86.
4.Hosseini-Zare MS, et al. Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice. Eur J Pharmacol. 2011 Nov 30;670(2-3):464-70.
5.Reber LL, et al. The AGC kinase inhibitor H89 attenuates airway inflammation in mouse models of asthma. PLoS One. 2012;7(11):e49512.
6.Liu M, Yang Y, Tan B, et al. Gαi and Gβγ subunits have opposing effects on dexmedetomidine-induced sedation[J]. European journal of pharmacology. 2018 Jul 15;831:28-37.
7.Xu C, Zhao W, Huang X, et al. TORC2/3-mediated DUSP1 upregulation is essential for human decidualization[J]. Reproduction. 2021, 1(aop).
8.Fu T, Chai B, Shi Y, et al. Fargesin inhibits melanin synthesis in murine malignant and immortalized melanocytes by regulating PKA/CREB and P38/MAPK signaling pathways[J]. Journal of Dermatological Science. 2019 Mar 28. pii: S0923-1811(19)30069-6.

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