VU0409551 (JNJ-46778212) (Synonyms: JNJ-46778212) |
Catalog No.GC18412
One-Click Copy Product Info
|
VU0409551 (JNJ-46778212) is a potent and selective biased positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGlu5 PAM; EC50=260nM).
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1363281-27-9
Sample solution is provided at 25 µL, 10mM.
_1-3.$$$39978408@51.jpg');)
_1-9.$$$38538795@65.jpg');)
_1-9.$$$39112701@51.jpg');)
_1-7.$$$37316672@70.jpg');)
_366-372.$$$36198801@70.jpg');)
.$$$38565142@65.jpg');)
_1867-1883.$$$33248023@67.jpg');)
_eads6055.$$$39977546@45.jpg');)
_eadm9805.$$$40080571@45.jpg');)
_eadj3020.$$$39666821@45.jpg');)
_1-20.$$$39757301@28.jpg');)
_1-24.$$$38898113@28.jpg');)
_273-287.$$$36806353@46.jpg');)
_1-16.$$$37156877@44.jpg');)
_1-19.$$$37460805@44.jpg');)
_1291-1307.$$$34518654@46.jpg');)
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.
| 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 | |
| Synonyms | JNJ-46778212 | ||
| Chemical Name | [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 | ||
| Formula | C20H17FN2O3 | M.Wt | 352.4 |
| Solubility | DMSO : 100 mg/mL (283.80 mM; Need ultrasonic) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
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 |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.50% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 23 reference(s) in Google Scholar.)