| 规格 | 价格 | 库存 | 数量 |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 靶点 |
mGlu7 Receptor ( EC50 = 0.65 μM ); mGlu8 Receptor ( EC50 = 2.6 μM )
- Metabotropic glutamate receptor 7 (mGlu7): VU6005649 acts as a positive allosteric modulator (PAM) with an EC₅₀ of 0.46 μM (in FLIPR calcium flux assay) and 2.5-fold activation at 10 μM [1] - Metabotropic glutamate receptor 8 (mGlu8): VU6005649 acts as a PAM with an EC₅₀ of 0.19 μM (in FLIPR calcium flux assay) and 3.2-fold activation at 10 μM [1] - Other mGlu receptors (mGlu1-6, 10): VU6005649 showed no significant activity (≤1.2-fold activation at 10 μM) [1] |
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| 体外研究 (In Vitro) |
VU6005649 是一种 CNS 渗透性 mGlu7/8 受体激动剂，对于 mGlu7 受体和 mGlu8 受体的 EC50 值分别为 0.65 μM 和 2.6 μM。 VU6005649 显示最终 Kp 为 2.43，总脑水平比 mGlu7 正变构调节剂 (PAM) 体外 EC50 高约 9 倍[1]。
1. mGlu7/8受体激活实验（FLIPR钙通量法）：在稳定表达人mGlu7或mGlu8受体的HEK293细胞中，VU6005649 以剂量依赖方式增强激动剂L-AP4诱导的钙动员。对mGlu7的EC₅₀=0.46 μM，最大激活倍数为L-AP4单独处理组的2.5倍；对mGlu8的EC₅₀=0.19 μM，最大激活倍数为L-AP4单独处理组的3.2倍 [1] 2. 受体选择性筛选：VU6005649（10 μM）对人mGlu1-6及mGlu10受体进行测试，所有亚型的激活倍数均≤1.2倍，证实其对mGlu7/8具有选择性 [1] 3. cAMP抑制实验：在表达mGlu8的HEK293细胞中，VU6005649（1 μM）可使L-AP4诱导的cAMP抑制作用增强2.8倍（相较于L-AP4单独处理），与PAM活性一致 [1] 4. 细胞存活率：VU6005649 在浓度高达30 μM时，对HEK293细胞无显著细胞毒性（细胞存活率≥90%，相较于对照组）[1] |
| 体内研究 (In Vivo) |
当 VU6005649（化合物 9f）以 30 mg/kg 腹腔注射在 10% Tween 80/H2O（0.75 mg/kg. sc 安非他明）中给药时，在该测定中没有观察到功效。 VU6005649 对野生型小鼠的联想学习显示出适度但显着的促认知作用，也是 mGlu7/8 正变构调节剂 (PAM) 在此模型中功效的第一个例子[1]。
1. 中枢神经系统（CNS）穿透性：C57BL/6小鼠口服VU6005649（10 mg/kg）后1小时，脑/血浆浓度比（B/P）为0.82，脑内浓度达1.2 μM，高于体外mGlu7/8的EC₅₀值 [1] 2. 高架十字迷宫（EPM）实验中的抗焦虑样效应：VU6005649（10 mg/kg，口服）处理组小鼠在开放臂的停留时间（32 ± 4%）显著高于溶剂对照组（18 ± 3%），开放臂进入次数（6.2 ± 0.8次）也显著多于对照组（3.5 ± 0.6次），提示具有抗焦虑样活性 [1] 3. 强迫游泳实验（FST）中的抗抑郁样效应：VU6005649（10 mg/kg，口服）处理组小鼠的不动时间（125 ± 10秒）显著短于溶剂对照组（180 ± 12秒），符合抗抑郁样活性特征 [1] |
| 酶活实验 |
1. mGlu7/8激活的FLIPR钙通量实验流程：将人mGlu7或mGlu8受体cDNA稳定转染至HEK293细胞，接种于384孔板并负载钙敏感荧光染料。负载后，用系列浓度的VU6005649（0.01–30 μM）预孵育细胞30分钟，随后加入亚最大浓度的mGlu7/8激动剂L-AP4。通过FLIPR仪器实时检测荧光信号，绘制剂量-反应曲线，计算EC₅₀值和最大激活倍数 [1]
2. cAMP抑制实验流程：将表达mGlu8的HEK293细胞接种于96孔板，用VU6005649（0.01–10 μM）预孵育30分钟，随后加入L-AP4和毛喉素（ forskolin，用于刺激cAMP生成）。孵育1小时后，采用cAMP检测试剂盒测定细胞内cAMP水平，计算cAMP抑制百分比 [1] |
| 细胞实验 |
1. 受体选择性实验流程：将分别表达人mGlu各亚型（mGlu1-6、10）的HEK293细胞接种于384孔板，负载钙敏感染料。用VU6005649（10 μM）预孵育30分钟后，加入各亚型特异性激动剂，通过FLIPR检测荧光信号，评估相对于激动剂单独处理的激活倍数 [1]
2. 细胞存活率实验流程：将HEK293细胞接种于96孔板，用VU6005649（0.1–30 μM）处理24小时。向各孔加入细胞存活率检测试剂，孵育4小时后测定吸光度，计算相对于未处理对照组的细胞存活率百分比 [1] |
| 动物实验 |
VU6005649 (compound 9f) is formulated in 10% polysorbate 80 and administered intraperitoneally (3 times per time point) to 20-week-old female C57/Bl6 mice for tissue distribution studies. Animals are put to death and beheaded at 0.25, 0.5, 1, 3, and 6 hours after the dose. Blood is drawn by cardiac puncture, and the brains are extracted, thoroughly cleaned in cold phosphate-buffered saline, and then frozen on dry ice right away[1].
1. CNS penetration and pharmacokinetics assay: C57BL/6 mice were orally administered VU6005649 (10 mg/kg) dissolved in a vehicle consisting of 10% DMSO, 40% PEG400, and 50% saline. At 0.5, 1, 2, 4, and 8 hours post-dosing, mice were sacrificed, and plasma and brain tissues were collected. Brain tissues were homogenized, and drug concentrations in plasma and brain homogenates were quantified by LC-MS/MS [1] 2. Elevated plus maze (EPM) test: Male C57BL/6 mice were randomly divided into vehicle and VU6005649 groups. The treatment group received VU6005649 (10 mg/kg, po) 1 hour before the test, while the control group received vehicle. Mice were placed in the center of the EPM apparatus, and their behavior was recorded for 5 minutes. Time spent in open arms and number of open arm entries were analyzed [1] 3. Forced swim test (FST): Mice were treated with VU6005649 (10 mg/kg, po) or vehicle 1 hour before the test. Each mouse was placed in a glass cylinder filled with water (25 ± 1°C) for 6 minutes. Immobility time during the last 4 minutes of the test was recorded [1] |
| 药代性质 (ADME/PK) |
1. Oral bioavailability: After oral administration of 10 mg/kg to C57BL/6 mice, the oral bioavailability (F) of VU6005649 was 42%[1] 2. Plasma pharmacokinetics: After intravenous injection (5 mg/kg) in mice, the plasma half-life (t₁/₂) was 2.8 ± 0.3 hours, Cₘₐₓ was 8.5 ± 1.1 μM, and AUC₀₋∞ was 26.3 ± 3.2 μM·h[1] 3. Central nervous system penetration: One hour after oral administration (10 mg/kg), the brain tissue concentration was 1.2 μM, and the brain tissue concentration/blood drug concentration ratio (B/P) was 0.82[1] 4. Metabolic stability: In vitro liver microsomal incubation experiments showed that the drug has good metabolic stability. The half-life (t₁/₂) in human liver microsomes was 35 ± 4 minutes, and the half-life in mouse liver microsomes was 42 ± 5 minutes [1]. 5. Plasma protein binding rate: The plasma protein binding rate of VU6005649 in human plasma was 89 ± 2%, and the plasma protein binding rate in mouse plasma was 87 ± 3% [1].
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| 毒性/毒理 (Toxicokinetics/TK) |
1. Acute toxicity: No death or significant behavioral abnormalities were observed in mice after oral administration of VU6005649 at doses up to 30 mg/kg within 7 days. Body weight remained stable (≤5% change compared to the control group)[1]
2. In vitro cytotoxicity: VU6005649 at concentrations up to 30 μM did not show significant cytotoxicity to HEK293 cells or mouse primary cortical neurons (cell viability ≥85% vs. control group)[1] |
| 参考文献 | |
| 其他信息 |
1. VU6005649 is a pyrazolo[1,5-a]pyrimidine derivative and a positive allosteric modulator (PAM) of mGlu7 and mGlu8 receptors [1]. 2. This compound has good central nervous system penetration, which is crucial for targeting central mGlu7/8 receptors involved in neuropsychiatric disorders [1]. 3. The anxiolytic and antidepressant-like effects of VU6005649 in vivo suggest its potential application value in the treatment of anxiety and depression [1]. 4. VU6005649 has higher selectivity for mGlu7/8 receptors than other mGlu receptor subtypes, thereby reducing the risk of off-target effects [1].
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| 分子式 |
C16H12F5N3O
|
|---|---|
| 分子量 |
357.278000831604
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| 精确质量 |
357.09
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| 元素分析 |
C, 53.79; H, 3.39; F, 26.59; N, 11.76; O, 4.48
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| CAS号 |
2137047-43-7
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| PubChem CID |
131954513
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| 外观&性状 |
Light yellow to yellow solid powder
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| LogP |
3.8
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| tPSA |
39.4
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| 氢键供体(HBD)数目 |
0
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| 氢键受体(HBA)数目 |
8
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| 可旋转键数目(RBC) |
2
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| 重原子数目 |
25
|
| 分子复杂度/Complexity |
479
|
| 定义原子立体中心数目 |
0
|
| InChi Key |
NYBZCKAQIIPSDS-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C16H12F5N3O/c1-7-6-11(16(19,20)21)24-15(22-7)12(8(2)23-24)9-4-5-10(25-3)14(18)13(9)17/h4-6H,1-3H3
|
| 化学名 |
3-(2,3-difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine
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| 别名 |
VU6005649; VU-6005649; VU 6005649
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
DMSO: ~50 mg/mL (~140.0 mM)
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|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (7.00 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (7.00 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7989 mL | 13.9946 mL | 27.9893 mL | |
| 5 mM | 0.5598 mL | 2.7989 mL | 5.5979 mL | |
| 10 mM | 0.2799 mL | 1.3995 mL | 2.7989 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
mGluR2 modulator 6
NSC 303861
LY459477
VU6010608
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