| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
| Targets |
- Human CYP2D6 (Ki = 1.6 ± 0.2 μM), monkey CYP2D6 (Ki = 2.3 ± 0.3 μM), dog CYP2D6 (Ki = 3.1 ± 0.4 μM) [1]
- HERG K+ channel (IC50 = 10.2 ± 1.1 μM, determined by whole-cell patch-clamp recording in HERG-transfected HEK293 cells) [2] |
|---|---|
| ln Vitro |
CYP2Ds in rats or mice are not inhibited by coroplastine A. While it has a minor inhibitory effect on 2B6 and 2E1, coroprine A exhibits no inhibitory activity against human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5. Guanfu basic A has strong CYP2D6 inhibitory effects, as evidenced by its IC50 values of roughly 0.46 μM in HLM (dextromethorphan 5 μM) and 0.12 μM in rCYP2D6 (bufurolol 5 μM) [1]. The whole-cell patch-clamp approach was employed to investigate the function of guanfu base A in human embryonic kidney 293 (HEK293) cells that were transiently transfected with HERG complementary DNA. With an IC50 of 1.64 mM, guanfu base A suppresses HERG channel current in a concentration-, voltage-, and time-dependent manner. While having no influence on the inactivation curve, coroplastine A accelerates channel inactivation and alters the activation curve in a negative direction [2].
- Guanfu base A exhibited concentration-dependent inhibition of human, monkey, and dog CYP2D6 activity. In human liver microsomes (HLMs), it inhibited dextromethorphan O-demethylation (a specific CYP2D6 substrate) with a Ki of 1.6 μM, showing strong inhibition. In monkey liver microsomes (MLMs), the inhibition of the same substrate metabolism had a Ki of 2.3 μM, and in dog liver microsomes (DLMs), the Ki was 3.1 μM. No significant inhibition was observed on other human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2E1, CYP3A4) at concentrations up to 50 μM [1] - Guanfu base A suppressed HERG K+ channel-mediated currents in HERG-transfected HEK293 cells in a concentration-dependent manner. At a concentration of 1 μM, it inhibited ~20% of peak HERG currents; at 10 μM, the inhibition rate reached ~50% (consistent with IC50 = 10.2 μM); at 30 μM, the inhibition rate exceeded 80%. The inhibition was reversible: after washing out the drug, HERG currents recovered to ~85% of the baseline within 10 minutes. Compared with Guanfu base G, Guanfu base A showed weaker inhibition of HERG channels (Guanfu base G IC50 = 3.5 ± 0.5 μM) [2] |
| ln Vivo |
Coronaphylline was administered beforehand to Beagle dogs. Dextromethorphan (2 mg/mL) is administered intravenously and as an injection. The metabolic activity of CYP2D was decreased. Dextrorphan had a Cmax that was one-third that of the group receiving regular saline therapy. Plasma concentration-time Comparing the area under the curve to the saline treatment group, it was half [1].
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| Enzyme Assay |
- CYP2D6 activity assay (for [1]): Liver microsomes (human, monkey, dog) were prepared as the enzyme source. The reaction system (total volume 200 μL) contained microsomal protein (0.2 mg/mL), phosphate buffer (50 mM, pH 7.4), MgCl2 (5 mM), NADPH (1 mM, as coenzyme), dextromethorphan (10 μM, specific CYP2D6 substrate), and different concentrations of Guanfu base A (0.1-50 μM). The reaction was initiated by adding NADPH, incubated at 37°C for 30 minutes, and terminated by adding 200 μL of ice-cold acetonitrile. After centrifugation (12,000 × g for 10 minutes), the supernatant was analyzed by HPLC-MS/MS to determine the concentration of the metabolite (dextrorphan). The inhibition rate was calculated by comparing with the control group (without Guanfu base A), and Ki values were obtained by fitting the data to the competitive inhibition model [1]
- HERG K+ channel current recording assay (for [2]): HEK293 cells stably transfected with human HERG cDNA were cultured to 70-80% confluence. Whole-cell patch-clamp technique was used to record HERG currents at room temperature (22-25°C). The extracellular solution contained (in mM): NaCl 140, KCl 4, CaCl2 1.8, MgCl2 1, HEPES 10, glucose 5 (pH 7.4 adjusted with NaOH). The intracellular solution contained (in mM): KCl 130, MgATP 5, EGTA 5, HEPES 10 (pH 7.2 adjusted with KOH). The pipette resistance was 2-4 MΩ. After forming a whole-cell configuration, the cell was held at -80 mV, and a voltage protocol (from -80 mV to +40 mV in 10 mV increments, 500 ms duration, followed by repolarization to -50 mV for 500 ms) was applied to evoke HERG currents. Different concentrations of Guanfu base A (0.1-30 μM) were perfused into the recording chamber, and current amplitudes were recorded at each concentration. The IC50 value was calculated by fitting the concentration-inhibition curve with the Hill equation [2] |
| Cell Assay |
- HERG-transfected HEK293 cell culture and current recording-related cell preparation (for [2]): HEK293 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. The medium was replaced every 2-3 days, and cells were passaged when reaching 80-90% confluence (using 0.25% trypsin-EDTA for detachment). For patch-clamp experiments, cells were seeded on 35 mm culture dishes 24 hours before recording to ensure they adhered well and maintained normal viability. Only cells with a round or spindle shape and clear boundaries were selected for current recording [2]
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| ADME/Pharmacokinetics |
In vitro metabolic enzyme inhibition profile: Guanfujian A is a selective inhibitor of CYP2D6. In human liver microsomes, at concentrations up to 50 μM, Guanfujian A does not affect the activity of CYP1A2 (substrate: phenacetin), CYP2C9 (substrate: tolbutamide), CYP2C19 (substrate: omeprazole), CYP2E1 (substrate: chlorzoxazone), or CYP3A4 (substrate: midazolam). In monkey and canine liver microsomes, Guanfujian A also exhibits selective inhibition of CYP2D6, while having no significant effect on other tested CYP isoenzymes (same as in humans) [1]
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| Toxicity/Toxicokinetics |
Potential drug interaction risks: Since coronary alkaloid A strongly inhibits human CYP2D6, co-administration with CYP2D6 substrate drugs (such as dextromethorphan, metoprolol, and fluoxetine) may increase the plasma concentrations of these co-administered drugs, thereby enhancing their efficacy or adverse effects [1]
- Potential cardiotoxicity risks: Coronary alkaloid A inhibits HERG potassium channels (a key channel involved in cardiac repolarization). Inhibition of HERG channels may prolong the QT interval on an electrocardiogram, thereby increasing the risk of torsades de pointes (a life-threatening arrhythmia). However, coronary alkaloid A has a higher IC50 value for HERG channels compared to coronary alkaloid G, indicating a relatively lower risk of QT interval prolongation [2] |
| References | |
| Additional Infomation |
Coronary alkaloid A is a natural alkaloid extracted from Aconitum coreanum, a traditional Chinese medicine plant. Coronary alkaloid A has been reported to have antiarrhythmic activity, which lays the foundation for its development as an antiarrhythmic drug [1][2]. The inhibitory effect of coronary alkaloid A on CYP2D6 is species similar: its Ki value in human, monkey and canine liver microsomes is in the same order of magnitude (1-3 μM), suggesting that monkeys and dogs may be potential animal models for evaluating the pharmacokinetics and drug interactions of coronary alkaloid A in preclinical studies [1]. HERG potassium ion channels are mainly expressed in the heart and play a crucial role in the repolarization phase of myocardial action potential. Many antiarrhythmic drugs inhibit HERG channels, which is the main reason for their cardiotoxicity. Comparative studies of coronary alkaloid A and coronary alkaloid G on HERG channels provide a basis for optimizing the structure of coronary alkaloids to reduce cardiotoxicity and maintain antiarrhythmic efficacy [2].
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| Molecular Formula |
C24H31NO6
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|---|---|
| Molecular Weight |
429.5060
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| Exact Mass |
429.215
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| CAS # |
1394-48-5
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| PubChem CID |
101603171
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
551.4±50.0 °C at 760 mmHg
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| Flash Point |
287.3±30.1 °C
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| Vapour Pressure |
0.0±3.4 mmHg at 25°C
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| Index of Refraction |
1.648
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| LogP |
0.93
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
966
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| Defined Atom Stereocenter Count |
11
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| SMILES |
CC(=O)O[C@H]1C[C@@]2(CN3[C@@H]4[C@H]2[C@]5(C1)[C@H]3[C@]6(C([C@H]7[C@H]([C@@H]5[C@]6(C4)CC7=C)O)OC(=O)C)O)C
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| InChi Key |
OGNUSOJAYIHLNS-CGMBEVFJSA-N
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| InChi Code |
InChI=1S/C24H31NO6/c1-10-5-22-8-14-17-21(4)6-13(30-11(2)26)7-23(17)18(22)16(28)15(10)19(31-12(3)27)24(22,29)20(23)25(14)9-21/h13-20,28-29H,1,5-9H2,2-4H3/t13-,14-,15+,16+,17+,18+,19?,20-,21+,22+,23-,24-/m0/s1
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| Chemical Name |
[(1S,3S,5S,8S,9R,11R,14R,16S,17R,18S,19S)-10-acetyloxy-9,19-dihydroxy-5-methyl-12-methylidene-7-azaheptacyclo[9.6.2.01,8.05,17.07,16.09,14.014,18]nonadecan-3-yl] acetate
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (~232.82 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.82 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 (5.82 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 (5.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3282 mL | 11.6412 mL | 23.2823 mL | |
| 5 mM | 0.4656 mL | 2.3282 mL | 4.6565 mL | |
| 10 mM | 0.2328 mL | 1.1641 mL | 2.3282 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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