| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Other Sizes |
| Targets |
- The primary target of Glucagon receptor antagonists-1 is the human Glucagon Receptor (GCGR), a G protein-coupled receptor (GPCR) involved in regulating glucose metabolism. The compound exhibits high affinity for GCGR, with an IC₅₀ value of 1.2 nM in competitive binding assays and an IC₅₀ value of 3.5 nM in functional assays (inhibiting glucagon-induced cAMP production) [1]
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| ln Vitro |
- Glucagon receptor antagonists-1 potently inhibits glucagon-mediated activation of GCGR in vitro. In CHO cells stably transfected with human GCGR, treatment with the compound (1–100 nM) dose-dependently reduces glucagon (100 pM)-induced intracellular cAMP accumulation, with an IC₅₀ of 3.5 nM [1]
- Structure-activity relationship (SAR) analysis shows that the Glucagon receptor antagonists-1 (a 4-aryl-pyridine derivative) achieves optimized activity through specific substituent modifications: (1) a 3,5-dichlorophenyl group at the 4-position of the pyridine ring enhances GCGR binding affinity; (2) a tertiary amino group at the 2-position of the pyridine ring improves water solubility and functional antagonism; (3) a methoxy group on the aryl ring reduces non-specific binding to other GPCRs. The optimized compound exhibits ~10-fold higher activity than unmodified 4-aryl-pyridine analogs (IC₅₀ of 3.5 nM vs. 38 nM for the parent compound) [1] - Glucagon receptor antagonists-1 shows high selectivity for GCGR over related GPCRs (e.g., GLP-1 receptor, GIP receptor). At concentrations up to 1 μM, it does not inhibit GLP-1-induced cAMP production in GLP-1 receptor-transfected cells, indicating minimal off-target activity [1] |
| Enzyme Assay |
-1. Prepare crude cell membranes from CHO cells stably expressing human GCGR. Resuspend membranes in binding buffer (containing Tris-HCl, MgCl₂, and bovine serum albumin) to a protein concentration of 10 μg/well.
2. Add serial dilutions of Glucagon receptor antagonists-1 (0.1 nM–1 μM) and a fixed concentration of [¹²⁵I]-labeled glucagon (0.5 nM) to the membrane suspension. Incubate the mixture at 25°C for 1 hour to allow binding equilibrium. 3. Filter the mixture through glass fiber filters pre-soaked in binding buffer to separate bound and free [¹²⁵I]-glucagon. Wash the filters three times with ice-cold washing buffer (Tris-HCl, MgCl₂) to remove unbound ligand. 4. Measure the radioactivity on the filters using a gamma counter. Calculate the percentage of specific binding by subtracting non-specific binding (in the presence of 1 μM unlabeled glucagon) from total binding. Plot the dose-response curve and determine the IC₅₀ value for Glucagon receptor antagonists-1 [1] - GCGR Functional Assay (cAMP Detection): 1. Seed CHO cells stably expressing human GCGR in 96-well plates at a density of 5×10⁴ cells/well. Incubate overnight in complete medium (DMEM + 10% fetal bovine serum) at 37°C with 5% CO₂. 2. Remove the medium and replace with serum-free medium containing 0.1% bovine serum albumin. Add serial dilutions of Glucagon receptor antagonists-1 (0.1 nM–1 μM) and incubate for 30 minutes at 37°C. 3. Add glucagon (final concentration 100 pM) to each well and continue incubating for 15 minutes to stimulate cAMP production. 4. Terminate the reaction by adding lysis buffer and measure intracellular cAMP levels using a homogeneous time-resolved fluorescence (HTRF) cAMP assay kit. Calculate the percentage of inhibition of glucagon-induced cAMP production and determine the IC₅₀ value [1] |
| References | |
| Additional Infomation |
Glucagon receptor antagonists-1 (GGR) are small molecule GCGR antagonists of the 4-arylpyridine class, designed for the treatment of type 2 diabetes. Their mechanism of action is to block glucagon signaling, thereby reducing hepatic glucose output (a key factor in hyperglycemia in type 2 diabetes)[1]. The development of GGR antagonists-1 focuses on optimizing the substituent pattern to overcome the limitations of early GCGR antagonists, such as low potency, poor selectivity and low water solubility. The 3,5-dichlorophenyl substituent at the 4-position of the pyridine ring is crucial for enhancing the hydrophobic interaction with the GCGR binding pocket, while the tertiary amine group can improve solubility, which is beneficial for in vitro studies and potential in vivo formulations[1].
- The high selectivity of glucagon receptor antagonist-1 for GCGR minimizes the risk of off-target effects (e.g., interference with GLP-1-mediated insulin secretion), which is a key advantage for its potential clinical application, as the GLP-1 receptor plays a beneficial role in glucose homeostasis [1]. |
| Molecular Formula |
C29H34FNO2
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|---|---|
| Molecular Weight |
447.58416
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| Exact Mass |
447.257
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| CAS # |
503559-84-0
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| PubChem CID |
66576985
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| Appearance |
White to off-white solid powder
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| Density |
1.094
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| LogP |
7.799
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
33
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| Complexity |
602
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=CC=C(C2=C(/C=C/C)C(C(C)C)=NC(C(C)C)=C2C(C)O)C(OCC3=CC=CC=C3)=C1
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| InChi Key |
HERVQUFQZXZOBU-YRNVUSSQSA-N
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| InChi Code |
InChI=1S/C29H34FNO2/c1-7-11-24-27(26(20(6)32)29(19(4)5)31-28(24)18(2)3)23-15-14-22(30)16-25(23)33-17-21-12-9-8-10-13-21/h7-16,18-20,32H,17H2,1-6H3/b11-7+
|
| Chemical Name |
1-[4-(4-fluoro-2-phenylmethoxyphenyl)-2,6-di(propan-2-yl)-5-[(E)-prop-1-enyl]pyridin-3-yl]ethanol
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| Synonyms |
Glucagon receptor antagonists-1
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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: ~50 mg/mL (~111.7 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.14 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 27.5 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: ≥ 2.75 mg/mL (6.14 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 27.5 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 | 2.2342 mL | 11.1712 mL | 22.3424 mL | |
| 5 mM | 0.4468 mL | 2.2342 mL | 4.4685 mL | |
| 10 mM | 0.2234 mL | 1.1171 mL | 2.2342 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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