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| Targets |
CCKBR agonist-2 specifically targets the cholecystokinin B receptor (CCKBR), a G protein-coupled receptor (GPCR). It exhibits a strong preference for activating the Gi subtype of G proteins, which inhibits adenylate cyclase and reduces cyclic AMP levels. This Gi-biased signaling profile distinguishes it from non-biased agonists that may also activate Gq and Gs pathways, thereby offering a more precise tool for studying specific downstream signaling events.
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| ln Vitro |
The compound effectively activates the CCKBR-Gi signaling pathway with an EC50 of 0.27 nM, demonstrating high potency. Crucially, it shows almost no detectable activity on the Gq and Gs signaling pathways at relevant concentrations. This high selectivity for Gi makes it a specific tool for dissecting the functional roles of Gi signaling downstream of CCKBR activation in various cellular contexts.
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| ln Vivo |
In a mouse model of Alzheimer's disease, CCKBR agonist-2 did not show significant protective effects. This outcome is consistent with its biased signaling profile, as the beneficial effects of CCKBR activation in cognitive disorders may be mediated through Gq or Gs pathways rather than Gi. This suggests that CCKBR agonist-2 is more suitable as a research tool for studying Gi signaling rather than as a direct therapeutic candidate for neurodegenerative diseases.
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| Enzyme Assay |
Radioligand binding assays are standard for measuring G protein-coupled receptor (GPCR) interaction. Membranes expressing recombinant human CCKBR are prepared and incubated with a radiolabeled CCKBR antagonist, such as [3H]-PD140376, in assay buffer (20 mM HEPES, 5 mM MgCl2, pH 7.4). Various concentrations of CCKBR agonist-2 are added to compete for binding. After incubation for 60 min at room temperature, bound radioligand is separated from free by vacuum filtration through GF/B filters, followed by scintillation counting. The inhibitory constant (Ki) is calculated from competition curves using Cheng-Prusoff equation.
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| Cell Assay |
Gi-mediated cAMP inhibition can be assessed in cells expressing recombinant CCKBR. Cells are seeded in 384-well plates and pre-incubated with forskolin (10 microM) and varying concentrations of CCKBR agonist-2 (0.1 pM - 10 microM). After 30 min at 37degC, intracellular cAMP levels are quantified using a homogeneous time-resolved fluorescence (HTRF) cAMP assay kit. The EC50 for Gi activation is determined as the concentration that reduces forskolin-stimulated cAMP production by 50%. This cell-based functional assay confirms the selective activation of the inhibitory Gi pathway.
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| Animal Protocol |
In the Abeta-induced Alzheimer's disease mouse model, cognitive impairment is induced in male C57BL/6 mice via intracerebroventricular injection of aggregated Abeta1-42 peptides. Mice are randomized to receive either CCKBR agonist-2 (1 mg/kg, intraperitoneally) or vehicle control once daily for 14 days. Behavioral tests including the Morris water maze and novel object recognition are performed during the final treatment days to assess spatial learning and memory. Hippocampal tissues are collected post-sacrifice for biochemical analyses (e.g., western blotting for synaptic proteins and inflammatory markers).
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| ADME/Pharmacokinetics |
As a small molecule (MW 273.28) with lipophilic properties, CCKBR agonist-2 is expected to have good blood-brain barrier permeability, a property common to many CCKBR ligands. Pharmacokinetic parameters are not fully detailed in the literature. Based on structural analogs, it likely has a short to moderate half-life in rodents (1-4 h) with moderate oral bioavailability. For in vivo studies, the compound is typically administered via intraperitoneal injection. Detailed PK studies would be required for full characterization.
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| Toxicity/Toxicokinetics |
Comprehensive toxicology data are not available. In the reported mouse AD model, CCKBR agonist-2 was well-tolerated at a dose of 1 mg/kg with no overt signs of toxicity. However, as with any novel chemical entity, further evaluation would be necessary for drug development. Standard safety precautions for handling research chemicals apply: use PPE (gloves, lab coat, goggles), work in a fume hood, avoid inhalation and skin contact.
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| References | |
| Additional Infomation |
CCKBR agonist-2 (CAS# 923714-61-8) is a research-grade chemical probe used for studying CCKBR biology. As a Gi-biased agonist, it is a valuable tool for dissecting the signaling pathways downstream of CCKBR activation, particularly the inhibitory Gi pathway. It is not an FDA-approved drug. For research use only, not for diagnostic or therapeutic applications.
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| Molecular Formula |
C15H15NO4
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| Molecular Weight |
273.28
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| CAS # |
923714-61-8
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| Appearance |
White to off-white solid powder
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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 : ~100 mg/mL (~365.93 mM; with sonication)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.6593 mL | 18.2963 mL | 36.5925 mL | |
| 5 mM | 0.7319 mL | 3.6593 mL | 7.3185 mL | |
| 10 mM | 0.3659 mL | 1.8296 mL | 3.6593 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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