Mavoglurant (AFQ056)
(Synonyms: (3AR,4S,7AR)-八氢-4-羟基-4-[2-(3-甲基苯基)乙炔基]-1H-吲哚-1-羧酸甲酯,AFQ056) 目录号 : GC30778
Mavoglurant (AFQ056)是一种结构选择性的、非竞争性的、具有口服活性的代谢型谷氨酸受体5（mGluR5）拮抗剂，IC50值为30nM。
Cas No.:543906-09-8
Sample solution is provided at 25 µL, 10mM.
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Mavoglurant (AFQ056) is a structurally selective, non-competitive, orally active antagonist of the metabotropic glutamate receptor 5 (mGluR5), with an IC50 value of 30nM [1]. mGluR5 is a transmembrane (TM) G protein-coupled receptor that is highly expressed in the cerebral cortex and hippocampus regions and plays a dominant role in brain diseases related to cognitive dysfunction [2]. Mavoglurant can be used to study fragile X syndrome (FXS) and Parkinson's disease-induced motor disorders caused by levodopa [3-4].
In vitro, treatment with Mavoglurant (1mM; 3 and 8 days) significantly reduced the transcriptional level of FMR1 in the FXS lymphoblastoid cell line [5]. Treatment with Mavoglurant (0.0625, 0.25, 0.5, 1.0 and 2.5μM; 0-75min) significantly reduced the dendritic APP expression in Fmr1 KO primary neurons, and decreased the length of dendritic spines and the density of immature dendritic spines (ciliary protrusions) [6].
In vivo, Mavoglurant (3.1mg/kg or 9.4mg/kg; i.v. or oral; single dose) treatment achieved the maximum concentration of Mavoglurant in rat plasma and brain 0.25 hours after oral administration, and reached the maximum concentration 0.08 hours after intravenous administration [1]. Mavoglurant (1, 3 and 10mg/kg/day; i.p.; single dose) treatment of mice with auditory epilepsy seizures effectively reduced the seizure and running symptoms of Fmr1 KO mice at doses of 3 and 10mg/kg, but was ineffective at 1mg/kg [6].
References:
[1] Vranesic I, Ofner S, Flor P J, et al. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization[J]. Bioorganic & Medicinal Chemistry, 2014, 22(21): 5790-5803.
[2] Kumar A, Dhull D K, Mishra P S. Therapeutic potential of mGluR5 targeting in Alzheimer's disease[J]. Frontiers in neuroscience, 2015, 9: 215.
[3] Petrov D, Pedros I, de Lemos ML, et al. Mavoglurant as a treatment for Parkinson's disease. Expert Opin Investig Drugs. 2014;23(8):1165-1179.
[4] Jacquemont S, Curie A, des Portes V, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3(64):64ra1.
[5] Tabolacci E, Pirozzi F, Gomez-Mancilla B, et al. The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro[J]. BMC medical genetics, 2012, 13(1): 13.
[6] Westmark PR, Dekundy A, Gravius A, Danysz W, Westmark CJ. Rescue of Fmr1KO phenotypes with mGluR5 inhibitors: MRZ-8456 versus AFQ-056. Neurobiol Dis. 2018;119:190-198.
Mavoglurant (AFQ056)是一种结构选择性的、非竞争性的、具有口服活性的代谢型谷氨酸受体5（mGluR5）拮抗剂，IC50值为30nM [1]。mGluR5是一种跨膜（TM）G蛋白偶联受体，在大脑皮层和海马体区域表达较高，在认知功能障碍相关的脑部疾病中占主导地位 [2]。Mavoglurant可用于研究脆性X综合征（FXS）和帕金森氏症中左旋多巴引起的运动障碍 [3-4]。
在体外，Mavoglurant（1mM; 3和8 days）处理显著下降了FXS淋巴母细胞系中FMR1的转录水平 [5]。Mavoglurant（0.0625、0.25、0.5、1.0和2.5μM; 0-75min）处理显著降低了Fmr1 KO原代神经元中树突性APP表达，并减少了树突棘的长度和未成熟树突棘（纤毛状突起）的密度 [6]。
在体内，Mavoglurant（3.1mg/kg or 9.4mg/kg; i.v. or oral; single dose）治疗通过口服给药后0.25小时Mavoglurant在大鼠血浆和大脑中达到了最大浓度，静脉给药后在0.08小时达到最大浓度 [1]。Mavoglurant（1、3和10mg/kg/day; i.p. ; single dose）治疗听源性癫痫发作小鼠，在剂量为3和10mg/kg时能有效减轻Fmr1 KO小鼠的癫痫发作和狂奔症状，但在1mg/kg剂量下无效[6]。
| Cell experiment [1]: | |
Cell lines | Lymphoblastoid cell lines |
Preparation Method | Lymphoblasts were grown in RPMI1640 medium supplemented with 10% fetal bovine serum, 2.5% of L-glutamine and penicillin/streptomycin at 37°C with 5% CO2. Treatments were done in T75 flask containing approximately 20 × 106 cells in a volume of 20ml. The effect of a single treatment with Mavoglurant was assessed at various times and concentrations. The drug was added daily at either 1, 10, 100 or 1,000μM concentration and cells were harvested to extract RNA and DNA after 3 or 8 days from the beginning of the treatment. Control cultures were sham-treated with the drug diluent. As positive controls for the FMR1 reactivation, parallel cultures were also treated with 1μM 5-aza-2-doxycytydine (5-azadC). Cell viability was assessed after 8 days of treatment. To assess the methylation status of the FMR1 gene promoter it was carried out a bisulphite sequencing analysis. |
Reaction Conditions | 1, 10, 100 and 1,000μM; 3 and 8 days |
Applications | Treatment with Mavoglurant (1mM) significantly reduced the transcriptional level of FMR1 in the FXS lymphoblastoid cell line. |
| Animal experiment [2]: | |
Animal models | Sprague–Dawley rats |
Preparation Method | Mavoglurant was administered as a microemulsion (made from a mixture of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, dl-α-tocopherol USP, propylene glycol USP and 12% ethyl alcohol) at a dose of 3.1mg/kg (10μmol/kg; application volume 1ml/kg) intravenously and 9.4mg/kg (30μmol/kg; application volume 2ml/kg) orally. After 0.08, 0.5, 1, 2, 4, 8 or 24h (i.v.) and 0.25, 0.5, 1, 2, 4, 8 or 24h (p.o.) (N = 6 rats per time-point per injection procedure) the animals were decapitated and trunk-blood was collected in EDTA-containing tubes and the brain was removed and immediately frozen on dry ice. Thereafter, plasma samples and brains were stored at −80°C until analysis. |
Dosage form | Single intravenous (3.1mg/kg) or oral (9.4mg/kg) |
Applications | Mavoglurant treatment achieved the maximum concentration of Mavoglurant in rat plasma and brain 0.25 hours after oral administration, and reached the maximum concentration 0.08 hours after intravenous administration |
References: | |
| Cas No. | 543906-09-8 | SDF | |
| 别名 | (3AR,4S,7AR)-八氢-4-羟基-4-[2-(3-甲基苯基)乙炔基]-1H-吲哚-1-羧酸甲酯,AFQ056 | ||
| Canonical SMILES | CC1=CC(C#C[C@]2(O)CCC[C@]3([H])[C@@]2([H])CCN3C(OC)=O)=CC=C1 | ||
| 分子式 | C19H23NO3 | 分子量 | 313.39 |
| 溶解度 | DMSO : ≥ 47 mg/mL (149.97 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 | 3.1909 mL | 15.9546 mL | 31.9091 mL |
| 5 mM | 638.2 μL | 3.1909 mL | 6.3818 mL |
| 10 mM | 319.1 μL | 1.5955 mL | 3.1909 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%
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