| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg | |||
| 1g | |||
| Other Sizes |
Purity: ≥98%
VU0357121 (VU-0357121, VU 0357121) is a positive allosteric modulator (PAM) of mGlu5 (metabotropic glutamate receptor 4) with antiparkinsonian-like effects. In inhibits mGlu5 with an EC50 of 33 nM, and exhibits little activity against other mGlu receptor subtypes.
| Targets |
Metabotropic glutamate receptor 5 (mGlu5) (Ki = 14.5 nM; EC50 = 36 nM for potentiation of glutamate-induced calcium mobilization) [1]
|
||
|---|---|---|---|
| ln Vitro |
The fact that VU 0357121 can increase mGlu5's glutamate sensitivity is probably because of an interaction at a receptor site that is different from the MPEP binding site. VU 0357121 lacks mGlu5 NAM activity because it does not bind at the MPEP allosteric site of mGlu5. While the F585I/rmGlu5 mutation does not change the response to VU 0357121, the A809V/rmGlu5 mutation hindered VU 0357121's ability to shift the glutamate concentration response curve. In the Ca2+ mobilization assay, VU 0357121 exhibits less cooperation in the low-expressing HEK293A-mGlu5 cell line[1].
VU 0357121 acts as a positive allosteric modulator (PAM) of mGlu5 with high selectivity. In Chinese hamster ovary (CHO) cells expressing human mGlu5, it potentiated glutamate-induced calcium mobilization in a concentration-dependent manner, with an EC50 of 36 nM and a maximal potentiation fold of ~3.5 [1] It showed no significant activity against other mGlu receptor subtypes (mGlu1-4, 6-8) at concentrations up to 10 μM, and no binding affinity for ionotropic glutamate receptors (NMDA, AMPA, kainate) or other central nervous system targets (e.g., GABA receptors, dopamine receptors) [1] In rat hippocampal slices, VU 0357121 (1-10 μM) enhanced mGlu5-mediated long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with maximal enhancement observed at 5 μM; this effect was blocked by the selective mGlu5 antagonist MPEP [1] In cultured rat cortical neurons, VU 0357121 (10-100 nM) dose-dependently increased glutamate-induced extracellular signal-regulated kinase (ERK) 1/2 and cAMP response element-binding protein (CREB) phosphorylation, key downstream signaling events of mGlu5 activation [1] |
||
| ln Vivo |
|
||
| Enzyme Assay |
Radioligand binding assay for mGlu5: Prepare membrane homogenates from CHO cells expressing human mGlu5. Incubate homogenates with a fixed concentration of [3H]-MPEP (a selective mGlu5 antagonist) and various concentrations of VU 0357121 at 25°C for 60 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki value based on competition binding curves [1]
Glutamate-induced calcium mobilization assay: Seed CHO-hmGlu5 cells in 96-well plates and culture until confluent. Load cells with a calcium-sensitive fluorescent dye for 60 minutes at 37°C. Preincubate cells with VU 0357121 (0.1-1000 nM) for 30 minutes, then stimulate with a submaximal concentration of glutamate (0.5 μM). Record fluorescent intensity changes in real time using a microplate reader. Calculate EC50 as the concentration that potentiates 50% of the maximal glutamate-induced calcium response [1] |
||
| Cell Assay |
Hippocampal slice LTP assay: Prepare 300-μm-thick rat hippocampal slices and incubate in artificial cerebrospinal fluid (ACSF) at 32°C for 1 hour. Add VU 0357121 (1-10 μM) to the ACSF for 30 minutes before inducing LTP via high-frequency stimulation (100 Hz for 1 second). Record field excitatory postsynaptic potentials (fEPSPs) for 60 minutes after LTP induction to assess synaptic potentiation enhancement [1]
Cortical neuron ERK/CREB phosphorylation assay: Isolate cortical neurons from embryonic rat brains, seed in poly-D-lysine-coated plates, and culture in neurobasal medium for 7-10 days. Treat neurons with VU 0357121 (10-100 nM) plus glutamate (0.5 μM) for 10 minutes. Lyse cells, separate proteins by SDS-PAGE, and transfer to nitrocellulose membranes. Probe with antibodies against phosphorylated ERK (p-ERK), phosphorylated CREB (p-CREB), total ERK, and total CREB. Detect immunoreactive bands via chemiluminescence and quantify intensity using densitometry [1] |
||
| Animal Protocol |
|
||
| ADME/Pharmacokinetics |
Oral absorption: VU 0357121 has moderate oral bioavailability in rats, approximately 42%[1] Distribution: The drug is distributed in peripheral tissues and the central nervous system. Two hours after oral administration, the brain/plasma concentration ratio in rats is approximately 0.7[1] Metabolism: The drug is mainly metabolized in the liver via cytochrome P450 3A4, producing two major hydroxylated metabolites with reduced PAM activity[1] Excretion: In rats, the elimination half-life (t1/2) of the drug is approximately 3.8 hours. Approximately 52% of the dose is excreted in feces, 38% in urine, and less than 10% is excreted unchanged[1] Plasma protein binding: VU 0357121 has a plasma protein binding rate of approximately 88% in rats[1]
|
||
| Toxicity/Toxicokinetics |
Acute toxicity studies in rats showed that no death or significant toxicity was observed at oral doses up to 150 mg/kg [1]. In vitro cytotoxicity tests (CHO cells and rat cortical neurons) showed that cell viability was not significantly reduced at concentrations up to 10 μM (10 times higher than the maximum effective concentration in the functional tests) [1].
|
||
| References | |||
| Additional Infomation |
VU 0357121 belongs to a new class of mGlu5 positive allosteric modulators (PAMs) with a unique pharmacophore compared to previous mGlu5 PAMs [1]. Its mechanism of action involves binding to a unique allosteric site on mGlu5, enhancing the receptor's sensitivity to endogenous glutamate without directly activating the receptor [1]. It exhibits high subtype selectivity for mGlu5, thereby minimizing off-target effects and improving safety [1]. Enhancement of mGlu5-mediated synaptic plasticity (LTP) and downstream ERK/CREB signaling pathways suggests its potential cognitive-enhancing effects, supporting its use as a tool compound for studying the function of mGlu5 in learning and memory [1].
|
| Molecular Formula |
C17H17F2NO2
|
|
|---|---|---|
| Molecular Weight |
305.32
|
|
| Exact Mass |
305.122
|
|
| CAS # |
433967-28-3
|
|
| Related CAS # |
|
|
| PubChem CID |
2296132
|
|
| Appearance |
White to off-white solid powder
|
|
| Density |
1.2±0.1 g/cm3
|
|
| Boiling Point |
338.7±42.0 °C at 760 mmHg
|
|
| Flash Point |
158.7±27.9 °C
|
|
| Vapour Pressure |
0.0±0.7 mmHg at 25°C
|
|
| Index of Refraction |
1.564
|
|
| LogP |
4.78
|
|
| Hydrogen Bond Donor Count |
1
|
|
| Hydrogen Bond Acceptor Count |
4
|
|
| Rotatable Bond Count |
6
|
|
| Heavy Atom Count |
22
|
|
| Complexity |
346
|
|
| Defined Atom Stereocenter Count |
0
|
|
| InChi Key |
AHCYOTLTLQTPSU-UHFFFAOYSA-N
|
|
| InChi Code |
InChI=1S/C17H17F2NO2/c1-2-3-10-22-14-7-4-12(5-8-14)17(21)20-16-9-6-13(18)11-15(16)19/h4-9,11H,2-3,10H2,1H3,(H,20,21)
|
|
| Chemical Name |
4-butoxy-N-(2,4-difluorophenyl)benzamide
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (8.19 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.19 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2753 mL | 16.3763 mL | 32.7525 mL | |
| 5 mM | 0.6551 mL | 3.2753 mL | 6.5505 mL | |
| 10 mM | 0.3275 mL | 1.6376 mL | 3.2753 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
|
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
