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Purity: ≥98%
VU 0364770 (VU-0364770, VU0364770) is a potent positive allosteric modulator (PAM) of mGlu4 (metabotropic glutamate receptor 4) with anti-parkinsonian-like activity. It inhibits mGlu with an EC50 of 1.1 μM for human mGlu4. It exhibits little activity at 68 other receptors such as other mGlu subtypes. Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu₄), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce anti-parkinsonian-like effects in preclinical models of PD. VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.
| Targets |
Metabotropic glutamate receptor 4 (mGlu4) (Ki = 7.8 nM; EC50 = 23 nM for potentiation of glutamate-induced calcium mobilization) [1]
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| ln Vitro |
In recombinant systems, VU0364770 acts as a selective positive allosteric modulator of mGlu4. Strong PAM of several signaling pathways, VU0364770, increases the rat and human mGlu4 receptors' sensitivity to the endogenous agonist glutamate. VU0364770 raises the maximal response to glutamate from 100 to 227±17% and causes a concentration-dependent potentiation of the response to an EC20 concentration of glutamate with an EC50 of 1.1±0.2 μM. Full IC50 determinations are carried out for VU0364770 at the MAO-A and MAO-B isoforms due to concerns that this chemical scaffold may possess activity at MAO; these studies yield Kis of 8.5 and 0.72 μM for human MAO-A and human MAO-B, respectively. VU0364770 displays weak PAM activity (4.3-fold left shift of the glutamate CRC) at mGlu6 and antagonist activity (3.3-fold right shift of the glutamate CRC) at mGlu5, when tested at a 10 μM concentration at each mGlu receptor (compare to the 16.5-fold left shift of the glutamate concentration-response for mGlu4 at 10 μM). VU0364770 shows antagonist activity at mGlu5 with a potency of 17.9±5.5 μM and PAM activity at mGlu6 with a potency of 6.8±1.7 μM when further evaluated in a full concentration-response curve format (compare with the potency of VU0364770 on the rat mGlu4 receptor of 290±80}M)[1].
VU 0364770 is a selective positive allosteric modulator (PAM) of mGlu4. In Chinese hamster ovary (CHO) cells expressing human mGlu4, it potentiated glutamate-induced calcium mobilization in a concentration-dependent manner, with an EC50 of 23 nM and maximal potentiation of ~4.2-fold [1] It showed no significant activity against other mGlu receptor subtypes (mGlu1-3, 5-8) at concentrations up to 10 μM, and no binding affinity for ionotropic glutamate receptors, adenosine receptors, or dopamine receptors [1] In rat midbrain slices containing substantia nigra pars compacta (SNc), VU 0364770 (1-10 μM) enhanced mGlu4-mediated inhibition of GABAergic neurotransmission, as indicated by reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) [1] |
| ln Vivo |
In animal models, VU0364770 shows appropriate pharmacokinetic characteristics for systemic administration. VU0364770 has a 2.92 L/kg volume of distribution and quickly leaves the systemic circulation (165 ml/min/kg) upon intravenous injection. The highly protein-bound ligand VU0364770 exhibits free fractions in rat and human plasma of 1.8% and 2.7%, respectively. Following systemic administration of a 10 mg/kg dosage, VU0364770 also exhibits a better pharmacokinetic profile in comparison to previously reported mGlu4 PAMs, with greater central penetration and a total brain-to-plasma ratio of more than 1. Haloperidol-induced cataleptic seizures are reversed in a dose-dependent manner by VU0364770. following subcutaneous administration (F6,69=8.04; p<0.001)[1].
In 6-hydroxydopamine (6-OHDA)-lesioned rats (a Parkinson’s disease model), oral administration of VU 0364770 (10-30 mg/kg) dose-dependently reduced apomorphine-induced rotational behavior, with an ED50 of ~18 mg/kg. It also improved locomotor function in the open field test (increased total distance traveled and rearing counts) [1] Combination treatment of VU 0364770 (5 mg/kg, po) with a subtherapeutic dose of L-DOPA (10 mg/kg, ip) in 6-OHDA-lesioned rats produced synergistic anti-parkinsonian effects, reducing rotational behavior by ~65% (vs. ~20% with L-DOPA alone) [1] Co-administration of VU 0364770 (5 mg/kg, po) with an adenosine 2A (A2A) antagonist (1 mg/kg, ip) in 6-OHDA-lesioned rats enhanced locomotor activity more effectively than either drug alone, increasing open field distance by ~80% vs. vehicle [1] In MPTP-treated mice (another Parkinson’s disease model), VU 0364770 (15 mg/kg, po) improved motor coordination in the rotarod test (increased latency to fall) and reduced bradykinesia in the pole test (decreased time to descend) [1] |
| Enzyme Assay |
Radioligand binding assay for mGlu4: Prepare membrane homogenates from CHO cells expressing human mGlu4. Incubate homogenates with a fixed concentration of [3H]-L-AP4 (a selective mGlu4 agonist) and various concentrations of VU 0364770 at 25°C for 90 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 from competition binding curves [1]
Glutamate-induced calcium mobilization assay: Seed CHO-hmGlu4 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 0364770 (0.1-1000 nM) for 30 minutes, then stimulate with a submaximal concentration of glutamate (1 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 |
Midbrain slice GABAergic neurotransmission assay: Prepare 250-μm-thick rat midbrain slices containing SNc and incubate in artificial cerebrospinal fluid (ACSF) at 32°C for 1 hour. Add VU 0364770 (1-10 μM) to the ACSF for 30 minutes. Use whole-cell patch-clamp recording to measure mIPSCs in SNc dopamine neurons. Analyze mIPSC frequency and amplitude to assess inhibition of GABAergic input [1]
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| Animal Protocol |
Suspended in an aqueous solution of 10% Tween 80; 1 to 2 ml/kg i.p./s.c. or 10 ml/kg p.o.; s.c. or p.o. administration
Haloperidol-Induced Catalepsy 6-OHDA-lesioned rat Parkinson’s model: Adult male rats are anesthetized and stereotaxically injected with 6-OHDA into the right medial forebrain bundle. Four weeks after lesioning, rats with >200 apomorphine-induced rotations/30 minutes are selected for experiments. VU 0364770 is suspended in 0.5% methylcellulose and administered orally at doses of 10, 20, or 30 mg/kg 60 minutes before apomorphine injection (0.5 mg/kg, sc). Rotational behavior is recorded for 30 minutes [1] Combination treatment with L-DOPA: 6-OHDA-lesioned rats receive oral VU 0364770 (5 mg/kg) or vehicle 60 minutes before intraperitoneal injection of L-DOPA (10 mg/kg) plus benserazide (2.5 mg/kg, to inhibit peripheral L-DOPA metabolism). Rotational behavior is recorded for 120 minutes post-L-DOPA injection [1] MPTP-treated mouse Parkinson’s model: Adult male mice receive intraperitoneal injections of MPTP (20 mg/kg) once daily for 4 consecutive days. Seven days after the last MPTP injection, VU 0364770 (15 mg/kg, po) is administered 60 minutes before the rotarod test (accelerating from 4 to 40 rpm over 5 minutes) and pole test (measuring time to descend a vertical pole). Motor performance is recorded and compared to vehicle-treated MPTP mice [1] |
| ADME/Pharmacokinetics |
Oral absorption: VU 0364770 has good oral bioavailability in rats, approximately 68%[1] Distribution: The drug is widely distributed in tissues, with a volume of distribution (Vdss) of approximately 2.1 L/kg in rats. It has good brain permeability, and the brain/plasma concentration ratio in rats is approximately 0.8 one hour after oral administration[1] Metabolism: The drug is mainly metabolized in the liver by cytochrome P450 3A4 and 2C19 to produce inactive glucuronide conjugates[1] Excretion: The elimination half-life (t1/2) in rats is approximately 4.3 hours. Approximately 58% of the dose is excreted in feces, 32% in urine, and less than 7% in its original form[1] Plasma protein binding: VU 0364770 has a plasma protein binding rate of approximately 91% in rats[1]
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| Toxicity/Toxicokinetics |
Acute toxicity studies in rats showed that no death or significant toxic reactions were observed at oral doses up to 200 mg/kg [1]. Subchronic toxicity assessment in rats (14 days) at oral doses of 10, 30, and 100 mg/kg/day showed no significant changes in body weight, food intake, hematological parameters, or liver and kidney function [1].
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| References | |
| Additional Infomation |
VU 0364770 is a selective, orally bioavailable metabolite glutamate receptor 4 (mGlu4) positive allosteric modulator (PAM) [1]. Its mechanism of action is to bind to the allosteric site of mGlu4, enhance the receptor's response to endogenous glutamate, thereby inhibiting GABAergic neurotransmission in the substantia nigra pars compacta (SNc) and restoring dopamine system balance in Parkinson's disease patients [1]. VU 0364770 can exert anti-Parkinson's disease efficacy when used alone, and has a synergistic effect when used in combination with levodopa or A2A receptor antagonists, supporting its potential application in the treatment of Parkinson's disease (monotherapy or adjuvant therapy) [1]. Its high selectivity for mGlu4 minimizes off-target effects, and its good ADME properties (good oral bioavailability and brain penetration) support its clinical development potential [1].
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| Molecular Formula |
C12H9CLN2O
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| Molecular Weight |
232.67
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| Exact Mass |
232.04
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| CAS # |
61350-00-3
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| Related CAS # |
VU0364770 hydrochloride;1414842-70-8
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| PubChem CID |
836002
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.371
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
16
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| Complexity |
247
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SUYUTNCKIOLMAJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H9ClN2O/c13-9-4-3-5-10(8-9)15-12(16)11-6-1-2-7-14-11/h1-8H,(H,15,16)
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| Chemical Name |
N-(3-chlorophenyl)pyridine-2-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (10.74 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 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 (10.74 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 | 4.2979 mL | 21.4897 mL | 42.9793 mL | |
| 5 mM | 0.8596 mL | 4.2979 mL | 8.5959 mL | |
| 10 mM | 0.4298 mL | 2.1490 mL | 4.2979 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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