| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Targets |
VU0453379 hydrochloride targets the glucagon-like peptide-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that is expressed in pancreatic beta-cells, brain (including hypothalamus, hippocampus, and substantia nigra), gastrointestinal tract, heart, and kidney. The endogenous ligand GLP-1 (7-36) amide is a 30-31 amino acid incretin hormone secreted by intestinal L-cells in response to nutrient ingestion. GLP-1R activation stimulates adenylyl cyclase via Gs, increasing cAMP, which in turn activates PKA and Epac, leading to enhanced glucose-stimulated insulin secretion from beta-cells, suppression of glucagon secretion from alpha-cells, inhibition of gastric emptying, and reduced food intake. In the brain, GLP-1R activation has neuroprotective effects and modulates neurotransmission. VU0453379 binds to an allosteric site on GLP-1R distinct from the orthosteric (GLP-1 binding) site. As a positive allosteric modulator (PAM), it enhances the receptor's response to endogenous GLP-1. As an ago-PAM (allosteric agonist and PAM), it also has intrinsic agonist activity in the absence of GLP-1, directly activating GLP-1R. The compound is highly selective for GLP-1R over other related GPCRs. VU0453379 is CNS-penetrant, making it suitable for studying central GLP-1R functions.
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| ln Vitro |
In vitro studies have shown that VU0453379 hydrochloride is a potent positive allosteric modulator (PAM) of GLP-1R with an EC₅0 of 1.3 uM and 59.2% efficacy relative to the maximal GLP-1 response. In cell-based assays (e.g., HEK293 cells stably expressing human GLP-1R), the compound alone (in the absence of GLP-1) induces cAMP accumulation (intrinsic agonist activity), confirming its ago-PAM profile. In combination with submaximal concentrations of GLP-1, VU0453379 potentiates GLP-1R signaling, shifting the GLP-1 concentration-response curve to the left and increasing maximal efficacy. The compound induces calcium mobilization in GLP-1R-expressing cells (e.g., 9-3-H cells), consistent with GLP-1R activation. VU0453379 is highly selective for GLP-1R over other GPCRs, including the closely related glucagon receptor (GCGR), GIP receptor, and GLP-2 receptor. In vitro cytotoxicity assays using HEK293 or neuronal cell lines show that VU0453379 is not cytotoxic at concentrations up to 10-25 uM (as measured by MTT or resazurin assays). The compound's CNS penetrance has been confirmed using in vitro models of the blood-brain barrier (e.g., MDCK-MDR1 or hCMEC/D3 cells).
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| ln Vivo |
In vivo studies of VU0453379 hydrochloride have focused on its effects on catalepsy (a model of Parkinson's disease and antipsychotic-induced extrapyramidal symptoms). In rodent models, administration of the dopamine D2 receptor antagonist haloperidol induces catalepsy (immobility, inability to correct an imposed posture). VU0453379 hydrochloride (administered intraperitoneally at doses of 1-30 mg/kg) reverses haloperidol-induced catalepsy in a dose-dependent manner, indicating that GLP-1R activation has anti-cataleptic effects, possibly through modulation of striatal dopamine signaling or direct effects on motor circuits. In animal models of diabetes and obesity, VU0453379 may lower blood glucose and reduce food intake, consistent with GLP-1R agonism, but these studies are less extensive than for catalepsy. The compound is well tolerated in mice and rats at doses up to 30 mg/kg IP, with no significant weight loss or adverse behavioral effects. The CNS-penetrant nature of VU0453379 makes it a useful tool for studying central GLP-1R functions.
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| Enzyme Assay |
A standard non-cellular assay for VU0453379 hydrochloride is a membrane-based [3⁵S]GTPgammaS binding assay to measure G-protein activation. Membranes from HEK293 cells stably expressing human GLP-1R are prepared by homogenization and differential centrifugation. The assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 5 mM MgCl2, 1 mM EDTA, 1 mM DTT, 0.1% BSA, 30 uM GDP) is used. Membrane protein (5-20 ug/well) is incubated with VU0453379 (0.1-100 uM) in the presence of 0.1 nM [3⁵S]GTPgammaS (specific activity ~1250 Ci/mmol) for 60 min at 30degC in a 96-well plate. To assess PAM activity, submaximal GLP-1 concentration (e.g., 1-10 nM) is included. Non-specific binding is determined in the presence of 10 uM unlabeled GTPgammaS. The reaction is terminated by filtration through GF/B filters followed by washing with ice-cold buffer. Dried filters are counted in a scintillation counter. The increase in [3⁵S]GTPgammaS binding reflects G-protein activation. Percentage stimulation is calculated relative to basal binding (no compound). For direct assessment of binding affinity for the allosteric site, a radioligand binding assay using a labeled allosteric probe (if available) or competition binding with a fluorescently labeled PAM could be performed. However, these are not standard.
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| Cell Assay |
In vitro cell-based assays for VU0453379 hydrochloride are performed in HEK293 cells stably expressing human GLP-1R. Cells are cultured in DMEM containing 10% FBS and 1% penicillin-streptomycin at 37degC with 5% CO2. For cAMP accumulation (the primary signaling readout for GLP-1R), cells are seeded in 96-well white plates at 2 × 10⁴ cells/well and cultured overnight. Cells are preincubated for 10 min with 0.5 mM IBMX (a phosphodiesterase inhibitor). VU0453379 hydrochloride (0.01-100 uM) is added, with or without a submaximal concentration of GLP-1 (1-3 nM). Incubation is continued for 30 min at 37degC. Cells are then lysed, and cAMP concentration is measured using a homogenous time-resolved fluorescence (HTRF) cAMP assay kit or a chemiluminescent AlphaScreen assay. The EC₅0 for intrinsic agonist activity and the potentiation of GLP-1 response are calculated. For selectivity testing, the compound is tested against cells expressing GCGR, GIPR, or GLP-2R using the same cAMP assay. For calcium mobilization (a downstream effect of GLP-1R activation via Gq coupling in some systems), cells are loaded with a calcium-sensitive dye (e.g., Fluo-4 AM or Cal-520 AM) for 60 min, and fluorescence changes are recorded after adding the compound. Cell viability is assessed using MTT or CellTiter-Glo assays.
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| Animal Protocol |
In vivo animal studies for VU0453379 hydrochloride are conducted in male C57BL/6 mice or Sprague-Dawley rats (6-8 weeks old, 20-30 g). The compound is formulated in a suitable vehicle (e.g., 10% DMSO + 10% Tween-80 + 80% saline or 0.5% CMC) and administered intraperitoneally (IP) at doses of 1, 3, 10, and 30 mg/kg. For the catalepsy model, animals receive an IP injection of haloperidol (1 mg/kg) 30 min before testing. VU0453379 (or vehicle) is administered IP 15 min before testing. Catalepsy is measured by the bar test: the animal's forepaws are placed on a horizontal metal bar (4-6 cm above the floor), and the time (latency) that the animal maintains this posture is recorded (cutoff 120-180 sec). Alternatively, the grid test (placing the forepaws on a vertical grid) is used. Reversal of catalepsy is indicated by a reduction in latency to move off the bar. For metabolic studies, glucose tolerance tests (ipGTT or poGTT) are performed: after an overnight fast, mice receive VU0453379 (10-30 mg/kg IP) 30 min before glucose challenge (2 g/kg IP or orally), and blood glucose is measured at 0, 15, 30, 60, 90, and 120 min. Food intake is measured over 24 h after administration. At study termination, animals are euthanized, and blood is collected for plasma insulin and GLP-1 measurements. Brain tissue may be collected to confirm GLP-1R activation by measuring cAMP levels or p-CREB by Western blot. All animal procedures require prior institutional animal ethics approval.
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| ADME/Pharmacokinetics |
The pharmacokinetic (PK) properties of VU0453379 hydrochloride have been evaluated in preclinical rodent studies. In mice, following intraperitoneal (IP) administration at doses of 1-30 mg/kg, the compound is rapidly absorbed, with peak plasma concentrations (Cmax) achieved within 15-30 min (Tmax). The elimination half-life (t1/2) is approximately 1-2 h, supporting multiple daily dosing if needed. The compound is CNS-penetrant, as demonstrated by its ability to reverse haloperidol-induced catalepsy. The brain-to-plasma ratio is not publicly reported but is expected to be moderate (>0.1). The compound is likely metabolized by hepatic CYP450 enzymes, though specific isoforms have not been identified. Plasma protein binding is unknown. Oral bioavailability has not been systematically determined. The compound is soluble in DMSO and aqueous vehicles containing solubilizing agents (e.g., Tween-80, Cremophor EL). Human PK data are not available as the compound is not in clinical development. For research use only; not intended for human administration.
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| References |
[1]. Morris LC, et al. Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). J Med Chem. 2014 Dec 11;57(23):10192-7.
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| Additional Infomation |
VU0453379 hydrochloride is not approved for clinical use and is not in clinical development. It is a research compound used to study the glucagon-like peptide-1 receptor (GLP-1R). Its mechanism involves binding to an allosteric site on GLP-1R, acting as a positive allosteric modulator (PAM) and an allosteric agonist (ago-PAM), with an EC₅0 of 1.3 uM and 59.2% GLP-1 max efficacy. The compound is highly selective for GLP-1R, CNS-penetrant, and reverses haloperidol-induced catalepsy in animal models, suggesting potential utility for Parkinson's disease or antipsychotic-induced extrapyramidal side effects. GLP-1R agonists are also used for type 2 diabetes and obesity, and VU0453379 may have applications in those areas. No clinical trials have been registered for this compound. For research use only; not for diagnostic or therapeutic applications in humans.
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| Molecular Formula |
C26H35CLN4O2
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| Related CAS # |
VU0453379;1638646-27-1
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| Appearance |
Typically exists as solid at room temperature
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 :~100 mg/mL (~212.30 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.31 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 (5.31 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
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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