VU0409551 (JNJ-46778212)是一种强效且选择性的偏向性代谢型谷氨酸受体5亚型正变构调节剂（mGlu5 PAM；EC50=260nM）。
Cas No.:1363281-27-9
Sample solution is provided at 25 µL, 10mM.
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VU0409551 (JNJ-46778212) is a potent and selective biased positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGlu5 PAM; EC50=260nM)[1-2]. VU0409551 selectively potentiates mGlu5-mediated Gaq signaling without modulating NMDAR currents. VU0409551 is used in research related to schizophrenia, Huntington's disease, Phelan-McDermid syndrome, and autism spectrum disorders[3-4].
In vitro, HEK293A cells expressing low levels of mGlu5 (HEK293A-mGlu5-low) were treated with VU0409551 (0.1nM-0.1µM) for 1 hour. VU0409551 induced calcium mobilization, mGlu5 accumulation, and ERK1/2 phosphorylation[5]. HEK293A cells expressing rat mGlu5 were treated with VU0409551 (0.1nM-10µM) for 5-60 minute, followed by a challenge with a maximal concentration of glutamate (100µM) or DHPG (30µM). VU0409551 potentiated the desensitization of DHPG-induced, mGlu5-mediated intracellular calcium mobilization[6].
In vivo, BACHD mouse models of Huntington's disease, aged 8-10 months, received daily intraperitoneal injections of VU0409551 (3mg/kg) for 8 days. VU0409551 ameliorated memory deficits in BACHD mice, increased mGluR5 expression at the plasma membrane, elevated the expression levels of synaptic plasticity-related genes (such as BDNF, Arc/Arg3.1, c-Fos, Syntaxin 1A, PSD-95), and increased dendritic spine density, maturity, and the number of presynaptic terminals[7]. Rats were treated with VU0409551 (1mg/kg to 450mg/kg; oral administration) for 7 days. VU0409551 significantly reversed amphetamine-induced hyperactivity and enhanced cognitive function in mice[8].
References:
[1] Hellyer SD, Sengmany K, Keller AN, et al. Probe dependence and biased potentiation of metabotropic glutamate receptor 5 is mediated by differential ligand interactions in the common allosteric binding site. Biochem Pharmacol. 2020 Jul;177:114013.
[2] Balu DT, Li Y, Takagi S, et al. An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology. 2016 Jul;41(8):2052-61.
[3] Brown J, Iacovelli L, Di Cicco G, et al. The comparative effects of mGlu5 receptor positive allosteric modulators VU0409551 and VU0360172 on cognitive deficits and signalling in the sub-chronic PCP rat model for schizophrenia. Neuropharmacology. 2022 May 1;208:108982.
[4] Brown J, Grayson B, Neill JC, et al. Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172. Cells. 2023 Mar 16;12(6):919.
[5] Sengmany K, Singh J, Stewart GD, et al. Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery. Neuropharmacology. 2017 Mar 15;115:60-72.
[6] Hellyer SD, Albold S, Sengmany K, et al. Metabotropic glutamate receptor 5 (mGlu5 )-positive allosteric modulators differentially induce or potentiate desensitization of mGlu5 signaling in recombinant cells and neurons. J Neurochem. 2019 Nov;151(3):301-315.
[7] Doria JG, de Souza JM, Silva FR, et al. The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease. J Neurochem. 2018 Oct;147(2):222-239.
[8] Conde-Ceide S, Martínez-Viturro CM, Alcázar J, et al. Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia. ACS Med Chem Lett. 2015 May 20;6(6):716-20.
VU0409551 (JNJ-46778212)是一种强效且选择性的偏向性代谢型谷氨酸受体5亚型正变构调节剂（mGlu5 PAM；EC50=260nM）[1-2]。VU0409551可选择性增强mGlu5与Gaq介导的信号传导而不调节NMDAR电流。VU0409551可用于精神分裂症、亨廷顿病、Phelan-McDermid综合征和自闭症谱系障碍的相关研究[3-4]。
在体外，VU0409551（0.1nM-0.1μM）处理低水平表达mGlu5的HEK293A细胞（HEK293A-mGlu5-low）1小时。VU0409551可诱导钙离子、mGlu5的累积和ERK1/2磷酸化[5]。VU0409551（0.1nM-10μM）处理表达大鼠mGlu5的HEK293A细胞5-60分钟，随后以最大浓度的谷氨酸盐（100μM）或DHPG（30μM）进行挑战。VU0409551能增强DHPG诱导的mGlu5介导的细胞内钙动员脱敏[6]。
在体内，VU0409551（3mg/kg）每日一次腹腔注射，用于处理8至10月龄的BACHD亨廷顿病模型小鼠，持续8天。VU0409551改善了BACHD小鼠的记忆缺陷，并增加了mGluR5在细胞质膜的表达，提高了与突触可塑性相关基因（如BDNF、Arc/Arg3.1、c-Fos、Syntaxin 1A、PSD-95）的表达水平，同时增加了树突棘的密度、成熟度以及突触前终末的数量[7]。VU0409551（1mg/kg至450mg/kg；口服）用于处理大鼠7天。VU0409551显著逆转了安非他明诱导的多动症，增强了小鼠的认知功能[8]。
| Cell experiment [1]: | |
Cell lines | HEK293A cells stably expressing rat mGlu5 (HEK293A-mGlu5-low) and primary cortical neuron cultures from E16 mice |
Preparation Method | HEK293A-mGlu5-low cells were maintained in DMEM supplemented with 5% FBS, 16 mM HEPES and 500µg/mL G418 at 37°C, 5% CO₂. For assays, cells were seeded in poly-D-lysine coated plates. Cells were treated with VU0409551. |
Reaction Conditions | 0.1nM-10μM; 5-60min. |
Applications | VU0409551 was a partial allosteric agonist for intracellular calcium mobilization and inositol monophosphate accumulation, and a full agonist for ERK1/2 phosphorylation, achieving a maximal response similar to the orthosteric agonist DHPG. |
| Animal experiment [2]: | |
Animal models | FVB/N-Tg(HTT*97Q)IXwy/J transgenic (BACHD) mice, and their wild-type (WT) littermates |
Preparation Method | VU0409551 was dissolved in 20% β-cyclodextrin. Mice received intraperitoneal (i.p.) injections of either the vehicle (20% β-cyclodextrin) or VU0409551 (3mg/kg) once daily for 8 consecutive days. Behavioral tests (novel object location and cued fear conditioning) were performed on days 7 and 8. |
Dosage form | 3mg/kg; i.p.; once daily for 8 days. |
Applications | Subchronic treatment with VU0409551 rescued the memory deficits exhibited by BACHD mice. VU0409551 reversed impairments in both novel object location recognition and cued fear conditioning tests. The treatment did not alter spontaneous locomotor activity or anxiety-related behavior. VU0409551 increased mGluR5 expression at the cellular plasma membrane, up-regulated synaptic plasticity-related genes (e.g., BDNF, Arc/Arg3.1, c-Fos, Syntaxin 1A, PSD-95), and enhanced dendritic spine density, maturity, and the number of pre-synaptic terminals. |
References: | |
| Cas No. | 1363281-27-9 | SDF | |
| 别名 | VU 0409551 | ||
| 化学名 | [6,7-dihydro-2-(phenoxymethyl)oxazolo[5,4-c]pyridin-5(4H)-yl](4-fluorophenyl)-methanone | ||
| Canonical SMILES | O=C(C1=CC=C(F)C=C1)N2CCC3=C(OC(COC4=CC=CC=C4)=N3)C2 | ||
| 分子式 | C20H17FN2O3 | 分子量 | 352.4 |
| 溶解度 | DMSO : 100 mg/mL (283.80 mM; Need ultrasonic) | 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。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8377 mL | 14.1884 mL | 28.3768 mL |
| 5 mM | 567.5 μL | 2.8377 mL | 5.6754 mL |
| 10 mM | 283.8 μL | 1.4188 mL | 2.8377 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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- Purity: >99.50% Appearance: A solid
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