产品描述

Lurasidone 是非典型的抗精神病药物，抑制Dopamine D2, 5-HT2A, 5-HT7, 5-HT1A 和去甲肾上腺素α2C，IC50分别为1.68 nM, 2.03 nM, 0.495 nM, 6.75 nM 和10.8 nM。

靶点

Dopamine D2

5-HT2A

5-HT7

5-HT1A

noradrenaline α2C

IC50

1.68 nM

2.03 nM

0.495 nM

6.75 nM

10.8 nM

体外研究

Lurasidone antagonizes dopamine-stimulated [35S]GTPγS binding at human dopamine D2L receptor in a concentration-dependent manner with a KB value of 2.8 nM. Lurasidone antagonizes 5-HT-stimulated cAMP accumulation in the CHO/h5-HT7 cells with a KB value of 2.6 nM. Lurasidone partially stimulates [35S]GTPγS binding to the membrane preparation for human 5-HT1A receptors with a maximum effect of 33%. Lurasidone dose-dependently increases the ratio of DOPAC/dopamine in rat frontal cortex and striatum.

体内研究

The inhibitory actions of Lurasidone on MAP-induced hyperactivity persists for more than 8 hours, and the ED50 values of the action at 1 hour, 2 hours, 4 hours, and 8 hours after the treatment are 2.3 mg/kg, 0.87 mg/kg, 1.6 mg/kg, and 5.0 mg/kg, respectively. Lurasidone (1 mg/kg–10 mg/kg) dose-dependently inhibits conditioned avoidance response in rats with ED50 of 6.3 mg/kg. Lurasidone dose-dependently inhibits TRY-induced forepaw clonic seizure and p-CAMP-induced hyperthermia in rats with ED50 of 5.6 mg/kg and 3.0 mg/kg, respectively. Lurasidone (0.3 mg/kg–30 mg/kg) dose-dependently and significantly increases the number of shocks received by rats in the Vogel’s conflict test with MED of 10 mg/kg. Lurasidone (3 mg/kg, 2 weeks) significantly suppresses hyperactivity behavior in olfactory bulbectomy model rats. Lurasidone (700 mg/kg–1000 mg/kg) slightly prolongs the duration of loss of righting reflexes elicited by hexobarbital (anesthesia) in mice in a dose-dependent manner.Lurasidone (30 mg/kg, p.o.) significantly and dose-dependently reverses the MK-801-induced impairment of the passive-avoidance response of rats.Lurasidone (3 mg/kg p.o.) potently reverses MK-801-induced learning impairment in the Morris water maze test in rats. Lurasidone (3 mg/kg p.o.) potently reverses MK-801-induced reference memory impairment and moderately but not significantly attenuates MK-801-induced working memory impairment in the radial-arm maze test.Lurasidone (10 mg/kg) treatment increases total BDNF mRNA levels in rat prefrontal cortex and, to less extent, in hippocampus. Lurasidone (10 mg/kg) significantly increases the levels of mature BDNF protein in rat prefrontal cortex, without affect the protein levels of the neurotrophin (both precursor and mature forms) in hippocampal extracts.

溶解性

DMSO 1 mg/mL，水 <1 mg/mL，乙醇 <1 mg/mL

稳定性

2年 -20°C粉状，6月-80°C溶于DMSO

特征

LY03009120是一种有效的泛Raf抑制剂，在A375细胞中对A-raf，B-Raf，和 C-Raf的IC50分别为44 nM，31-47 nM，和 42 nM。Phase 1。

特性

LGX818是有效的选择性RAF激酶抑制剂，对野生型BRAF几乎没有作用活性。

IC50 & Target

体外

LY3009120抑制A375和 HCT116细胞的生长，IC50分别为9.2和220 μM。LY3009120抑制酪氨酸激酶KDR，IC50为3.9 μM。

体内

在负荷BRAF V600E ST019VR PDX肿瘤的大鼠体内，LY3009120 (15 or 30 mg/kg, p.o.)剂量依赖性抑制肿瘤生长。在负荷A375异种移植物的裸鼠体内，LY3009120 (3到50 mg/kg, p.o.)单剂量口服治疗剂量依赖性抑制磷酸-ERK，4.36 mg/kg剂量下抑制50%磷酸- ERK (EC50)，68.9 ng/mL或165 nM血浆浓度下达到50%磷酸- ERK (EC50) 抑制率。

激酶实验

使用KiNativ试验测定激酶活性:
化合物在A375细胞裂解物中使用基于ATP的探针在5 µM下筛选。IC50值以微摩尔单位表示。细胞沉淀重悬浮在4体积裂解缓冲液[25 mM Tris pH 7.6，150 mM NaCl，1% CHAPS，1% Tergitol NP-40 型，1% v/v 磷酸酶抑制剂混合物II]中，使用尖端超声波仪声处理，并均质化。裂解产物通过100,000 g下离心分离30分钟除去。澄清的裂解液通过0.22 μM注射过滤器和凝胶过滤到反应缓冲液[20 mM Hepes pH 7.8，150 mM NaCl，0.1% triton X-100，1% v/v 磷酸酶抑制剂混合物II]。抑制剂处理和探针标记之前，将终浓度为20 mM 的MnCl2加入裂解液。用于IC50测定的终抑制剂浓度为10，1，0.1，和 0.01 μM。ATP竞争性实验在1,000，100，10，和1 μM ATP下进行。所有抑制剂的处理在室温下进行。

细胞实验

• Cell lines: A375 和 HCT116 细胞
• Concentrations: 0.51 μM
• Incubation Time: 67 h
• Method: 简而言之，细胞在DMEM高浓度葡萄糖中生长，用10%胎牛血清和1%青霉素/链霉素/L-谷氨酰胺增补，在37℃，5% CO2，和95%湿度下培育。允许细胞扩增到70-95%的融合度。连续稀释的测试化合物分配加入到384孔黑色透明底板。每孔加入包含625个细胞的50 μL完全生长培养基。板在37℃，5% CO2，和95%湿度下培育67小时。然后，10 μL包含440 μM 刃天青的PBS溶液加入板的每孔中，板在37℃，5% CO2，和95%湿度下再培育5小时。板在Synergy2阅读器上使用540 nm激发波长和600 nm发射波长读取。得到的数据使用Prism软件分析以计算IC 50值。
  (Only for Reference)

动物实验

• Animal Models: 负荷BRAF V600E ST019VR PDX肿瘤的雌性 NIH裸鼠
• Formulation: 20% 环糊精，25 mM 磷酸盐，pH2.0
• Dosages: 30 mg/kg
• Administration: p.o.
  (Only for Reference)

MB3600

Encorafenib (LGX818)

MB3922

CEP-32496

MB4072

ZM 336372

1 mg

5 mg

10 mg

1 mM

2.3557 mL

11.7783 mL

23.5566 mL

5 mM

0.4711 mL

2.3557 mL

4.7113 mL

10 mM

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