MRK 016
目录号 : GC16528
An inverse agonist of α5 subunit-containing GABAA receptors
Cas No.:783331-24-8,342652-67-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Kinase experiment: |
L(tk-) cells expressing human recombinant GABAA receptors containing β3- and γ2-subunits in combinatioon with various α-subunits are harvested and binding performed. The displacement of [3H]Ro 15-1788 binding by the test compounds (MRK-016, etc.) is measured in GABAA receptors containing eigher an α1-, α2-, α3-, and α5-subunit and from the IC50 and the Ki is calculated assuming respective Kd values of [3H]Ro 15-1788 binding of 0.92, 1.05, 0.58 and 0.45 nM at the α1-, α2-, α3-, and α5-subtypes. Nonspecific binding is defined by the inclusion of 10 μM flunitrazepam for the α1-, α2-, α3-, and α5-subtypes. The percentage inhibition of [3H]Ro 15-1788, the IC50 and the Ki values are calculated using ActivityBase[1]. |
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Animal experiment: |
Mice[1]The proconvulsant potential MRK-016 is determined in this assay. The convulsant is pentylenetetrazole which is dosed at 15 mg/mL with an infusion rate of 0.2 mL/min. This rate is chosen to ensure that drug-naive mince reach the terminal convulsion sign within 1 min. MRK-016 is dosed intraperitoneally (ip) at a concentration of 1, 3, and 10 mg/kg in 70% PEG 300[1]. |
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References: [1]. Chambers MS, et al. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. J Med Chem. 2004 Nov 18;47(24):5829-32. |
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MRK-016 is a selective, orally bioavailable inverse agonist of GABAA α5 receptor, with an EC50 of 3 nM for GABAA α5, and Kis of 0.83, 0.85, 0.77 and 1.4 nM for human GABAA α1β3γ2, GABAA α2β3γ2, GABAA α3β3γ2, and GABAA α5β3γ2, respectively; MRK-016 also readily penetrates the CNS.
MRK-016 is a selective, orally bioavailable inverse agonist of GABAA α5 receptor, with an EC50 of 3 nM for GABAA α5, and Kis of 0.83, 0.85, 0.77 and 1.4 nM for human GABAA α1β3γ2, GABAA α2β3γ2, GABAA α3β3γ2, and GABAA α5β3γ2, respectively[1][2]. MRK-016 is a full inverse agonist at the α5-subtype, shows very weak affinity at the GABAA α4β3γ2-subtype (Ki 395 ± 173 nM) and is essentially inactive at the GABAA α6β3γ2 receptor (Ki > 4000 nM)[1]. MRK-016 shows a weak effect on GABAA α4β3γ2 with a Ki of 400 nM. MRK-016 (100 nM) alao increases long-term potentiation in mouse hippocampal slices[2].
MRK-016 does not enhance pentylenetetrazole-induced convulsions at 10 mg/kg via ip, or cause seizures at 30 mg/kg, via po for 20 days in mice. MRK-016 shows no obvious anxiogenic-like effects in rats at doses that occupy >95% of benzodiazepine (BZ) binding sites. MRK-016 (0.3, 1, and 3 mg/kg, p.o.) dose-dependently improves performance of rats hippocampal-dependent memory task[1]. MRK-016 (0.3-30 mg/kg, p.o.) causes good receptor occupancy in rats. MRK-016 (0.3, 1, or 3 mg/kg p.o.) shows cognition-enhancing activity in the delayed matching-to-position version of the Morris water maze. MRK-016 (1, 3, or 10 mg/kg i.p.) does not produce kindling in mice[2]. MRK-016 (3 mg/kg, i.p.) protects against LPS-induced learning/memory decrements in mice[3].
References:
[1]. Chambers MS, et al. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. J Med Chem. 2004 Nov 18;47(24):5829-32.
[2]. Atack JR, et al. In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist. J Pharmacol Exp Ther. 2009 Nov;331(2):470-84.
[3]. Eimerbrink MJ, et al. Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin. Behav Brain Res. 2015 Jul 15;288:50-3.
| Cas No. | 783331-24-8,342652-67-9 | SDF | |
| 化学名 | 3-(9-(tert-butyl)-8-((1-methyl-1H-1,2,4-triazol-5-yl)methoxy)pyrazolo[1,5-d][1,2,4]triazin-2-yl)-5-methylisoxazole | ||
| Canonical SMILES | CC(C)(C)C1=C2N(C(C3=NOC(C)=C3)=NN=C2)N=C1OCC4=NC=NN4C | ||
| 分子式 | C17H20N8O2 | 分子量 | 368.39 |
| 溶解度 | <36.84mg/ml in DMSO | 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 | 2.7145 mL | 13.5726 mL | 27.1451 mL |
| 5 mM | 0.5429 mL | 2.7145 mL | 5.429 mL |
| 10 mM | 0.2715 mL | 1.3573 mL | 2.7145 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。