VU6025733
VU6025733 (AG06827) is a highly selective, orally active and blood-brain barrier-penetrant positive allosteric modulator of the muscarinic acetylcholine receptor subtype M4 (M4 mAChR). VU6025733 exerts a potentiating effect on acetylcholine-induced receptor activation with an EC50 of 23 nM for hM4 and 55 nM for rM4. VU6025733 shows high selectivity over other muscarinic acetylcholine receptor subtypes, dose-dependently reduces amphetamine-induced hyperlocomotion in rats. VU6025733 is applicable to the research of schizophrenia, Parkinson's disease, and Alzheimer's disease.
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- Formule: C20H18D5N5O3
- Masse moléculaire:386.46
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Protocole
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Description
In Vitro
VU6025733 (10-point serial dilutions (1:3)) potently potentiates human M4/Gqi5-CHO cells (EC50 = 33 nM) and rat M4/Gqi5-CHO cells (EC50 = 62 nM), while showing no activity in human or rat M1, M2, M3, or M5 muscarinic receptor-expressing CHO cells[1].
VU6025733 inhibits hERG channels with an IC50 of 4.6 μM[1].
VU6025733 induces cytotoxic effects in HepaRG 3D spheroids, including reduced glutathione content and cellular ATP, with MEC values of 9.7 μM and 4.2 μM, respectively[1].
VU6025733 decreases oxygen consumption rate (MEC = 2.0 μM) and increases extracellular acidification rate (MEC = 7.1 μM) in HepG2 cells, indicating electron transport chain inhibition[1].
VU6025733 has high brain penetration potential with no P-glycoprotein efflux, as shown by an efflux ratio of 0.80 and Papp (A-B) of 12.7 × 10-6 cm/s in MDCKII-MDR1 cells[1].
VU6025733 shows minimal inhibition of CYP1A2, CYP2C9, and CYP3A4 (IC50 ≥ 19.3 μM) and moderate inhibition of CYP2D6 (IC50 = 8.4 μM)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
Parmacokinetics
| Species | Dose | Route | T1/2 | MRT | CLplasma | Vss | Plasma Concentration | CLunbound | Brain Concentration | Brain distribution | Tmax | Cmax | AUC0-∞ | Bioavailability |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rat[1] | 1 mg/kg | i.v. | 5.67 h | 3.83 h | 5.26 mL/min/kg | 1.21 L/kg | / | / | / | / | / | / | / | / |
| Rat[1] | 3 mg/kg | p.o. | / | / | / | / | / | / | / | / | 0.75 h | 1783 ng/mL | 6753 ng·h/mL | 74.1 % |
| Rat[1] | 10 mg/kg | p.o. | / | / | / | / | 3974 ng/mL | 39.7 ng/mL | 1086 ng/g | 17.4 ng/g | / | / | / | / |
| Rat[1] | 15 mg/kg | p.o. | / | / | / | / | 6463 ng/mL | 64.6 ng/mL | 1587 ng/g | 25.4 ng/g | / | / | / | / |
| Rat[1] | 30 mg/kg | p.o. | / | / | / | / | 11477 ng/mL | 115 ng/mL | 3157 ng/g | 50.5 ng/g | / | / | / | / |
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley (male)[1]
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Dosage:10 mg/kg; 15 mg/kg; 30 mg/kg
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Administration:p.o.; single administration
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Result:Produced a 25.6% reversal of induced hyperlocomotion, with a mean unbound brain concentration of 17.4 ng/g.
Produced a 34.0% reversal of induced hyperlocomotion, with a mean unbound brain concentration of 25.4 ng/g.
Produced a 39.7% reversal of induced hyperlocomotion, with a mean unbound brain concentration of 50.5 ng/g.
Significantly reduced total ambulation.
Chemical Information
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Unlabeled CAS 3084929-79-0
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Masse moléculaire 386.46
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Formule C20H18D5N5O3
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SMILES
CC1=C(C)C(N2CCC(OC3=CC=C4OC([2H])([2H])C([2H])([2H])OC4=C3)([2H])CC2)=NN5C1=NN=C5
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Synonyms
AG06827
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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Human pluripotent stem cell midbrain dopaminergic neuron differentiation
Human pluripotent stem cells are directed toward midbrain dopaminergic neurons by first inducing a neural floor-plate-like progenitor state, then patterning cells with ventralizing SHH signaling and midbrain/WNT-FGF cues, and finally maturing progenitors into neurons expressing dopaminergic markers such as TH, NURR1/NR4A2, PITX3, DAT/SLC6A3, VMAT2/SLC18A2, GIRK2/KCNJ6, FOXA2, LMX1A, and EN1. The main readouts are loss of pluripotency, acquisition of FOXA2+/LMX1A+ midbrain floor-plate progenitors, emergence of βIII-tubulin+/MAP2+ neurons, and production of TH+ dopaminergic neurons with molecular, dopamine-release, and electrophysiological features of midbrain dopaminergic identity.
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Alzheimer’s Disease Modeling
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive functions and loss of specific types of neurons and synapses. Alzheimer's symptoms can be simulated in mice by injecting drugs (such as Aβ) or genetically modified.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
VU6025733 Related Classifications
HY-181559S Related Classifications
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Keywords
- VU6025733
- AG06827
- VU 6025733
- VU-6025733
- AG 06827
- AG-06827
- mAChR
- M4 muscarinic acetylcholine receptor positive allosteric modulator
- orally active
- blood-brain barrier penetrant
- potentiate acetylcholine-mediated M4 mAChR activation
- hM4/Gqi5-CHO cells
- MDCKII-MDR1 transfected cells
- HepaRG 3D spheroids
- HepG2 cells
- rat amphetamine-induced hyperlocomotion model
- SD rat
- schizophrenia
- Parkinson's disease
- Alzheimer's disease
- Inhibitor
- inhibitor
- inhibit