2. GPCR/G Protein Neuronal Signaling
  3. mAChR
  4. 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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VU6025733

VU6025733 Chemical Structure

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VU6025733 Related Antibodies

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Description

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[1].

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.

VU6025733 Related Antibodies
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

VU6025733 (10-30 mg/kg; p.o.; single administration) produces a robust, dose-dependent blockade of induced hyperlocomotion in male Sprague-Dawley rats, with a minimum effective dose of 10 mg/kg and up to 39.7% reversal at the highest tested dose[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Sprague-Dawley (male)[1]
Dosage: 10 mg/kg; 15 mg/kg; 30 mg/kg
Administration: p.o.; single administration
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.
Molecular Weight

386.46

Formula

C20H18D5N5O3
Unlabeled CAS
SMILES

CC1=C(C)C(N2CCC(OC3=CC=C4OC([2H])([2H])C([2H])([2H])OC4=C3)([2H])CC2)=NN5C1=NN=C5
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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VU6025733 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

VU6025733AG06827VU 6025733VU-6025733AG 06827AG-06827mAChRMuscarinic acetylcholine receptorM4 muscarinic acetylcholine receptor positive allosteric modulatororally activeblood-brain barrier penetrantpotentiate acetylcholine-mediated M4 mAChR activationhM4/Gqi5-CHO cellsMDCKII-MDR1 transfected cellsHepaRG 3D spheroidsHepG2 cellsrat amphetamine-induced hyperlocomotion modelSD ratschizophreniaParkinson's diseaseAlzheimer's diseaseInhibitorinhibitorinhibit

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