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VU0650786 is a novel, potent, selective and CNS permeable negative allosteric modulator of metabotropic glutamate receptor subtype 3 (mGlu3 NAM), with an IC50 of 392 nM. In rodents, VU0650786 exhibits anxiolytic and antidepressant properties.
| Targets |
mGluR3 ( IC50 = 392 nM )
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|---|---|
| ln Vitro |
VU0650786 is a potent and selective negative allosteric modulator of mGlu₃, with an IC₅₀ of 392 nM in a calcium mobilization assay. It showed no functional activity at mGlu₂ or mGlu₅ up to 30 µM, representing >76-fold selectivity. In a broad ancillary pharmacology panel of 68 targets, it only showed significant inhibition (65%) at 5-HT₂B in a radioligand binding assay at 10 µM. However, a follow-up functional assay confirmed no agonist or antagonist activity at 5-HT₂B up to 10 µM. The compound exhibited high permeability in MDR1-MDCK cells with no evidence of P-glycoprotein-mediated efflux. It showed weak inhibition of human cytochrome P450 enzymes (CYP2C9 IC₅₀ = 25.6 µM; >30 µM for CYP1A2, 2D6, 3A4). [1]
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| ln Vivo |
VU0650786 (VU786) (i.p., 30 mg/kg) diminishes thalamocortical long-term depression (LTD), decreases passive coping in acute models of antidepressant-like activity in inducible cFos-EGFP mice, and increases the proportion of c-Fos-positive cells by about 4-fold[2]. It also improves synaptic strength in cone cell subpopulations[2].
Viu0650786 (compound 106) in rats: pharmacokinetic characteristics[1]. In a mouse marble burying assay (a model for anxiety/obsessive-compulsive behavior), VU0650786 (10, 30, 56.6 mg/kg, IP) produced a dose-dependent and statistically significant reduction in marble burying, with near-complete inhibition at the highest dose. The estimated unbound brain Cmax at the 10 mg/kg dose was 564 nM (~1.5-fold over the functional IC₅₀). [1] In a rat forced swim test (a model of depression), VU0650786 (30 and 56.6 mg/kg, IP) significantly decreased immobility time at the 56.6 mg/kg dose. The estimated unbound brain Cmax at this dose was 2.3 µM (~6-fold over the functional IC₅₀). [1] |
| Enzyme Assay |
The functional activity of VU0650786 at mGlu receptors was assessed using cell-based fluorescence assays measuring receptor-mediated calcium mobilization. For mGlu₃ and mGlu₅, assays utilized cell lines stably expressing the rat receptor and the promiscuous G-protein Gα₁₅. The effect on the orthosteric agonist concentration-response curve was measured to determine IC₅₀ values for NAM activity or EC₅₀ values for PAM activity. Selectivity versus other mGlu receptors was determined by measuring the fold-shift of the respective agonist CRC in the presence of 10 µM VU0650786. [1]
A radioligand binding panel against 68 clinically relevant GPCRs, ion channels, kinases, and transporters was used to assess ancillary pharmacology. A significant hit (5-HT₂B) was followed up with a functional cell-based IP1 accumulation assay to confirm lack of functional activity. [1] Inhibition of human cytochrome P450 enzymes (CYP1A2, 2C9, 2D6, 3A4) was assessed using a cocktail assay in human liver microsomes with specific probe substrates. [1] |
| Cell Assay |
The primary mGlu₃ functional assay was performed in a cell line stably expressing rat mGlu₃ and Gα₁₅. Cells were plated in assay plates and loaded with a calcium-sensitive fluorescent dye. After dye loading, cells were treated with test compounds followed by an EC₂₀ concentration of glutamate. Calcium mobilization was measured fluorometrically. Concentration-response curves were generated to determine IC₅₀ values for NAMs. A similar protocol was used for mGlu₅ and mGlu₂ selectivity assays. [1]
Permeability and P-glycoprotein efflux potential were assessed using Madin-Darby canine kidney cells transfected with the human MDR1 gene. Bidirectional permeability (apical-to-basal and basal-to-apical) was measured, and the efflux ratio was calculated. [1] The functional assay for 5-HT₂B activity measured agonist- or antagonist-induced IP1 accumulation in a recombinant cell line. [1] |
| Animal Protocol |
Rat cassette pharmacokinetics study: Compounds (including VU0650786) were administered intravenously (0.2 mg/kg) as a cassette in a solution of 9% ethanol, 37% PEG 400, 54% DMSO. Blood samples were collected serially for plasma concentration analysis. [1]
Rat single-compound IV and oral PK study: For definitive IV PK, VU0650786 was administered (1.0 mg/kg, IV) in a solution of 10% ethanol, 50% PEG 400, 40% saline. For oral bioavailability, it was administered (3.0 mg/kg, PO) as a fine microsuspension in 0.1% Tween 80 and 0.5% methylcellulose in water. Blood samples were collected over time. [1] Rat tissue distribution study: VU0650786 was administered intraperitoneally (10 mg/kg) as a fine homogeneous suspension either in 10% ethanol and 90% PEG 400 or in 0.1% Tween 80/0.5% methylcellulose in water. Animals were euthanized 15 minutes post-dose, and plasma and brain tissues were collected for concentration measurement. [1] Mouse tissue distribution and PK study: VU0650786 was administered intraperitoneally (10 mg/kg) as a fine microsuspension in 0.1% Tween 80 and 0.5% methylcellulose in water. For tissue distribution, animals were euthanized 30 minutes post-dose for plasma and brain collection. For full PK, blood samples were collected serially after dosing. [1] Mouse marble burying assay: Male CD-1 mice were pretreated with VU0650786 (10, 30, 56.6 mg/kg, IP) or vehicle (10% Tween 80 in water) 15 minutes before being placed in a cage with marbles. The number of marbles buried after 30 minutes was counted. [1] Rat forced swim test: Male Sprague-Dawley rats were pretreated with VU0650786 (30, 56.6 mg/kg, IP) or vehicle (10% Tween 80 in water) 30 minutes before being placed in a water-filled cylinder. Immobility time was recorded during a 6-minute test session. [1] |
| ADME/Pharmacokinetics |
VU0650786 showed moderate clearance in rats (plasma clearance after intravenous injection CLplasma = 30 mL/min/kg). The steady-state volume of distribution (Vss) was 1.4 L/kg, and the terminal half-life (t₁/₂) was 49 min. The oral bioavailability in rats was 60%. [1]
This compound has excellent central nervous system penetration. In rats, the brain plasma ratio (Kp) was 1.7 and the free brain plasma ratio (Kp,uu) was 1.0 after intraperitoneal injection, indicating that equilibrium was reached and no obvious transport proteins were involved. In mice, Kp was 3.6 and Kp,uu was 0.78. [1] In rats, plasma protein binding was moderate (free fraction Fu = 0.083 in plasma; 0.052 in brain homogenate), and high in mice (Fu = 0.163 in plasma; 0.035 in brain homogenate). [1] After intraperitoneal injection (10 mg/kg) in rats, plasma Cmax was 4.57 µM, Tmax was 12.3 min, and AUC0-∞ was 11.5 µM·h. In mice (10 mg/kg, intraperitoneal injection), plasma Cmax was 4.48 µM, Tmax was 30 min, and AUC0-∞ was 7.26 µM·h. [1] In vitro metabolic stability in rat liver microsomes predicted moderate hepatic clearance. [1] |
| Toxicity/Toxicokinetics |
In the rodent studies described, no acute toxicity or side effects were reported at the doses used (up to 56.6 mg/kg). [1]
VU0650786 showed negligible drug interaction potential with major human cytochrome P450 enzymes (CYP1A2, 2C9, 2D6, 3A4), with IC₅₀ values >30 µM for all enzymes except CYP2C9 (IC₅₀ = 25.6 µM). [1] Although initial radioligand binding assays suggested an interaction with the 5-HT₂B receptor (65% inhibition at 10 µM), functional assays confirmed that it did not have agonist or antagonist activity, thus alleviating concerns about the potential cardiotoxicity of 5-HT₂B receptor agonists. [1] |
| References |
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| Additional Infomation |
VU0650786 was discovered through optimization of a 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compound, which was initially identified from cross-screening of mGlu₅ positive allosteric modulators. [1]
It is a highly selective mGlu₃ negative allosteric modulator (NAM) with drug-like pharmacokinetic properties, suitable as a tool compound for in vivo rodent studies. [1] Efficacy of the compound in the forced swimming test suggests potential antidepressant activity, while efficacy in the marble-buried test suggests potential anti-anxiety or anti-obsessive-compulsive activity. These effects have previously been observed in non-selective mGlu₂/₃ antagonists, suggesting that selective mGlu₃ inhibition may contribute to these therapeutic benefits. [1] The compound is not a P-glycoprotein-mediated efflux substrate and has high passive permeability. [1] |
| Molecular Formula |
C18H15CLFN5O2
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|---|---|
| Molecular Weight |
387.795405626297
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| Exact Mass |
387.09
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| CAS # |
1809085-30-0
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| PubChem CID |
122190433
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
544
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H]1CN(C(=O)C2=CC(=NN12)COC3=NC=C(C=C3)Cl)C4=C(N=CC=C4)F
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| InChi Key |
RXRVCJFGSOVYLG-LLVKDONJSA-N
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| InChi Code |
InChI=1S/C18H15ClFN5O2/c1-11-9-24(14-3-2-6-21-17(14)20)18(26)15-7-13(23-25(11)15)10-27-16-5-4-12(19)8-22-16/h2-8,11H,9-10H2,1H3/t11-/m1/s1
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| Chemical Name |
(7R)-2-[(5-chloropyridin-2-yl)oxymethyl]-5-(2-fluoropyridin-3-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one
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| Synonyms |
VU-0650786; VU 0650786; VU0650786
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: ~250 mg/mL (~644.7 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 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: ≥ 2.08 mg/mL (5.36 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 20.8 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 | 2.5786 mL | 12.8932 mL | 25.7865 mL | |
| 5 mM | 0.5157 mL | 2.5786 mL | 5.1573 mL | |
| 10 mM | 0.2579 mL | 1.2893 mL | 2.5786 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.
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