Guanfu base A
(Synonyms: 关附甲素) 目录号 : GC64448
Guanfu base A 是一种从 Aconitum coreanum 中分离的抗心律失常的生物碱，是一种有效的非竞争性 CYP2D6 抑制剂，对人肝微粒体 (HLM) 的 Ki 为 1.20 μM，对人重组体 (rCYP2D6) 的 Ki 为 0.37 μM。Guanfu base A 也是 CYP2D 的有效竞争抑制剂，对猴子和狗的微粒体的 Ki 分别为 0.38 μM，2.4 μM。Guanfu base A 还能抑制 HERG 通道电流。
Cas No.:1394-48-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Guanfu base A is an antiarrhythmic alkaloid isolated from Aconitum coreanum and is a potent noncompetitive CYP2D6 inhibitor, with a Ki of 1.20 μM in human liver microsomes (HLMs) and a Ki of 0.37 μM for the human recombinant form (rCYP2D6). Guanfu base A is also a potent competitive inhibitor of CYP2D in monkey (Ki of 0.38 μM) and dog (Ki of 2.4 μM) microsomes[1]. Guanfu base A also inhibits HERG channel current[2].
Guanfu base A has no inhibitory activity on mouse or rat CYP2Ds. Guanfu base A does not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but shows slight inhibition of 2B6 and 2E1[1].Guanfu base A is a potent inhibitor of CYP2D6, with an IC50 recorded at ~0.46 μM in HLM (Dextromethorphan 5 μM) and 0.12 μM in rCYP2D6 (Bufuralol 5 μM)[1]. The effects of Guanfu base A is investigated in human embryonic kidney 293 (HEK293) cells transiently transfected with HERG complementary DNA using a whole-cell patch clamp technique. Guanfu base A inhibits HERG channel current in concentration-, voltage-, and time-dependent manners with an IC50 of 1.64 mM. Guanfu base A shifts the activation curve in a negative direction and accelerated channel inactivation but shows no effect on the inactivation curve[2].
Beagle dogs treated intravenously with Dextromethorphan (2 mg/mL) after pretreatment with Guanfu base A injection shows reduced CYP2D metabolic activity, with the Cmax of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group[1].
[1]. Sun J, et al. Guanfu base A, an antiarrhythmic alkaloid of Aconitum coreanum, Is a CYP2D6 inhibitor of human, monkey, and dog isoforms. Drug Metab Dispos. 2015 May;43(5):713-24.
[2]. Huang X, et al. Comparative effects of Guanfu base A and Guanfu base G on HERG K+ channel. J Cardiovasc Pharmacol. 2012 Jan;59(1):77-83.
| Cas No. | 1394-48-5 | SDF | Download SDF |
| 别名 | 关附甲素 | ||
| 分子式 | C24H31NO6 | 分子量 | 429.51 |
| 溶解度 | 储存条件 | 4°C, away from moisture and light | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The Inhibition by Guanfu base A of Neuropathic Pain Mediated by P2Y12 Receptor in Dorsal Root Ganglia
ACS Chem Neurosci 2019 Mar 20;10(3):1318-1325.PMID:30475578DOI:10.1021/acschemneuro.8b00399.
Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) is involved in mechanical and thermal hyperalgesia. The upregulated P2Y12 receptor expressed in SGCs of the DRG participates in the nociceptive transmission of neuropathic pain. Guanfu base A (GFA) has been reported to exhibit antiarrhythmic and anti-inflammatory effects. In this study, we explored the effects of GFA on P2Y12 receptor-mediated mechanical and thermal hyperalgesia in chronic constriction injury (CCI) rats. Sprague-Dawley rats were randomly divided into sham operation group (Sham), CCI operation group (CCI), CCI rats treated with Guanfu base A group (CCI + GFA) and control rats treated with GFA group (Ctrl + GFA). Mechanical withdrawal threshold and thermal withdrawal latency were measured. P2Y12 expression in L4-L6 dorsal root ganglion (DRG) was detected by quantitative real-time PCR and Western blot. After CCI treatment, mechanical and thermal hyperalgesia and the expression values of P2Y12 receptor mRNA and protein in DRG were increased. Dual-labeling immunofluorescence showed that the coexpression of P2Y12 receptor and glial fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased compared to sham rats. GFA relieved mechanical and thermal hyperalgesia in the CCI rats, decreased the expression of P2Y12 mRNA and protein and phosphorylation of p38 MAPK in the DRG, and increased the ADP-downregulated cAMP concentrations in HEK293 cells transfected with P2Y12 plasmid. After CCI rats were treated with GFA, the coexpression of P2Y12 receptor and GFAP in the DRG was significantly decreased compared to the untreated CCI group. Thus, downregulating the P2Y12 receptor relieved mechanical and thermal hyperalgesia in the CCI rats.
Comparative effects of Guanfu base A and Guanfu base G on HERG K+ channel
J Cardiovasc Pharmacol 2012 Jan;59(1):77-83.PMID:21934630DOI:10.1097/FJC.0b013e318236e380.
Background: Guanfu base A (GFA) and Guanfu base G (GFG) are chemicals isolated from Aconitum coreanum. The potassium channel encoded by the human ether-a-go-go related gene (HERG) plays an important role in repolarization of the cardiac action potential. The purpose of the present study was to investigate the effects of GFA and GFG on the HERG channel and its structure-function relationship. Methods: The effects of GFA and GFG were investigated in human embryonic kidney 293 (HEK293) cells transiently transfected with HERG complementary DNA using a whole-cell patch clamp technique. Results: GFA and GFG inhibited HERG channel current in concentration-, voltage-, and time-dependent manners. The IC50 for GFA and GFG was 1.64 mM and 17.9 μM, respectively. Both GFA and GFG shifted the activation curve in a negative direction and accelerated channel inactivation but showed no effect on the inactivation curve. Moreover, GFG also accelerated channel recovery from inactivation. Conclusions: Both GFA and GFG blocked HERG channel current. This effect was stronger after GFG treatment rather than GFA treatment. This blockade was dependent on open and inactivated channel states. These results indicate that GFA could be a rather promising antiarrhythmic drug without severe side effects, whereas GFG could cause QT prolongation and requires further research.
Guanfu base A, an antiarrhythmic alkaloid of Aconitum coreanum, Is a CYP2D6 inhibitor of human, monkey, and dog isoforms
Drug Metab Dispos 2015 May;43(5):713-24.PMID:25681130DOI:10.1124/dmd.114.060905.
Guanfu base A (GFA) is a novel heterocyclic antiarrhythmic drug isolated from Aconitum coreanum (Lèvl.) rapaics and is currently in a phase IV clinical trial in China. However, no study has investigated the influence of GFA on cytochrome P450 (P450) drug metabolism. We characterized the potency and specificity of GFA CYP2D inhibition based on dextromethorphan O-demethylation, a CYP2D6 probe substrate of activity in human, mouse, rat, dog, and monkey liver microsomes. In addition, (+)-bufuralol 1'-hydroxylation was used as a CYP2D6 probe for the recombinant form (rCYP2D6), 2D1 (rCYP2D1), and 2D2 (rCYP2D2) activities. Results show that GFA is a potent noncompetitive inhibitor of CYP2D6, with inhibition constant Ki = 1.20 ± 0.33 μM in human liver microsomes (HLMs) and Ki = 0.37 ± 0.16 μM for the human recombinant form (rCYP2D6). GFA is also a potent competitive inhibitor of CYP2D in monkey (Ki = 0.38 ± 0.12 μM) and dog (Ki = 2.4 ± 1.3 μM) microsomes. However, GFA has no inhibitory activity on mouse or rat CYP2Ds. GFA did not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but showed slight inhibition of 2B6 and 2E1. Preincubation of HLMs and rCYP2D6 resulted in the inactivation of the enzyme, which was attenuated by GFA or quinidine. Beagle dogs treated intravenously with dextromethorphan (2 mg/ml) after pretreatment with GFA injection showed reduced CYP2D metabolic activity, with the Cmax of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group. This study suggests that GFA is a specific CYP2D6 inhibitor that might play a role in CYP2D6 medicated drug-drug interaction.
Safety, heart specificity, and therapeutic effect evaluation of Guanfu base A-loaded solid nanolipids in treating arrhythmia
Drug Deliv Transl Res 2018 Oct;8(5):1471-1482.PMID:30062563DOI:10.1007/s13346-018-0542-4.
Guanfu base A·HCl (GFA·HCl) solution, approved by the China Food and Drug Administration (CFDA) in 2005, has been used in the treatment of arrhythmia. However, the poor targeting and absorption of GFA·HCl have severely affected its clinical application. In this study, a nanolipid-based, Guanfu base A (GFA) delivery system was designed to improve the deficiency of GFA·HCl and realize better clinical effect. The GFA-loaded solid nanolipids (GFASN) with a core/shell structure, composed of Poloxamer 188, lecithin, and medium-chain fatty acid, were prepared using a high-pressure homogenate emulsification method. Results showed that GFASN possessed well morphology and stability during the process of lyophilization and rehydration at 220-260 nm. Safety evaluation revealed that ear vein injection of GFASN (14 mg/kg) were safe enough and of good biocompatibility. More importantly, GFASN can better alleviate the arrhythmia of rats, especially in ventricular ectopia and ventricular tachycardia, than GFA·HCl solution. Pharmacokinetic behaviors and targeting evaluation in mice demonstrated that nanolipids can help GFA achieve longer circulation time in blood and better heart specificity. Collectively, these promising findings suggested that this kind of nanolipids was an ideal delivery carrier for GFA in the treatment of cardiovascular disease.
Pharmacokinetics of guanfu base I, an active metabolite of Guanfu base A, in rats
Biol Pharm Bull 2005 Aug;28(8):1363-5.PMID:16079474DOI:10.1248/bpb.28.1363.
A liquid chromatographic-mass spectrometric (LC-MS) method was developed and validated for determination of guanfu base I (GFI), and the pharmacokinetics of GFI in Sprague-Dawley rats was examined. The method was linear in the 0.05-20 mug/ml concentration range (r=0.9994). The recovery of guanfu base I was more than 80%. The intraday and interday precision, expressed as the relative standard deviation (RSD), was generally good (<15%). After i.v. dosing, plasma GFI concentration declined in a bi-phasic manner with a terminal elimination half-life of 2.49 h. The total plasma clearance values was 1.46 l/h/kg. After oral dosing, the plasma GFI concentration reached a maximum within 0.5 h. The absolute bioavailability of GFI was 71.31%.