Azumolene
(Synonyms: 阿珠莫林,EU4093 free base) 目录号 : GC61493
A muscle relaxant
Cas No.:64748-79-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Azumolene is a muscle relaxant that inhibits the release of calcium from skeletal muscle sarcoplasmic reticulum.1,2 It inhibits a component of store-operated calcium entry (SOCE) that is coupled to the skeletal muscle ryanodine receptor, with 20 ?M azumolene causing a 70% reduction in SOCE in myotubes.3,4 Azumolene has utility in countering muscle dysfunction associated with malignant hyperthermia.4
1.Palnitkar, S.S., Michelson, J.R., Louis, C.F., et al.Pharmacological distinction between dantrolene and ryanodine binding sites: Evidence from normal and malignant hyperthermia-susceptible porcine skeletal muscleBiochem. J.326 (Pt 3)847-852(1997) 2.Leslie, G.C., and Part, N.J.The effect of EU4093 (azumolene sodium) on the contraction of intrafusal muscle in the soleus muscle of the anaesthetized ratBr. J. Pharmacol.97(4)1151-1156(1989) 3.Zhao, X., Weisleder, N., Han, X., et al.Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptorJ. Biol. Chem.281(44)33477-33486(2006) 4.Yarotskyy, V., Protasi, F., and Dirksen, R.T.Accelerated activation of SOCE current in myotubes from two mouse models of anesthetic- and heat-induced sudden deathPLoS One8(10)1-12(2013)
| Cas No. | 64748-79-4 | SDF | |
| 别名 | 阿珠莫林,EU4093 free base | ||
| Canonical SMILES | O=C1NC(CN1/N=C/C2=NC=C(C3=CC=C(Br)C=C3)O2)=O | ||
| 分子式 | C13H9BrN4O3 | 分子量 | 349.14 |
| 溶解度 | DMSO: 13.89 mg/mL (39.78 mM) | 储存条件 | Store at -20°C |
| 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 | 2.8642 mL | 14.3209 mL | 28.6418 mL |
| 5 mM | 0.5728 mL | 2.8642 mL | 5.7284 mL |
| 10 mM | 0.2864 mL | 1.4321 mL | 2.8642 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。
Synchronizing systolic calcium release with Azumolene in an experimental model
Heart Rhythm O2 2022 Jun 15;3(5):568-576.PMID:36340488DOI:10.1016/j.hroo.2022.06.001.
Background: Post-defibrillation myocardial contractile dysfunction adversely affects the survival of patients after cardiac arrest. Attenuation of diastolic calcium (Ca2+) overload by stabilization of the cardiac ryanodine receptor (RyR2) is found to reduce refibrillation after long-duration ventricular fibrillation (LDVF). Objective: In the present study, we explored the effects of RyR2 stabilization by Azumolene on systolic Ca2+ release synchrony and myocardial contractility. Methods: After completion of baseline optical mapping, Langendorff-perfused rabbit hearts were subjected to global ischemia followed by reperfusion with Azumolene or deionized distilled water (vehicle). Following reperfusion, LDVF was induced with burst pacing. In the first series of experiments (n = 16), epicardial Ca2+ transient was analyzed for Ca2+ transient amplitude alternans and dispersion of Ca2+ transient amplitude alternans index (CAAI). In the second series of experiments following the same protocol (n = 12), ventricular contractility was assessed by measuring the left ventricular pressure. Results: Ischemic LDVF led to greater CAAI (0.06 ± 0.02 at baseline vs 0.12 ± 0.02 post-LDVF, P < .01) and magnitude of dispersion of CAAI (0.04 ± 0.01 vs 0.09 ± 0.01, P < .01) in control hearts. In azumolene-treated hearts, no significant changes in CAAI (0.05 ± 0.01 vs 0.05 ± 0.01, P = .84) and dispersion of CAAI (0.04 ± 0.01 vs 0.04 ± 0.01, P = .99) were noted following ischemic LDVF. Ischemic LDVF was associated with reduction in left ventricular developed pressure (100% vs 36.8% ± 6.1%, P = .002) and dP/dtmax (100% vs 45.3% ± 6.5%, P = .003) in control hearts, but these reductions were mitigated (left ventricular developed pressure: 100% vs 74.0% ± 8.1%, P = .052, dP/dtmax: 100% vs 80.8% ± 7.9%, P = .09) in azumolene-treated hearts. Conclusion: Treatment with Azumolene is associated with improvement of systolic Ca2+ release synchrony and myocardial contractility following ischemic LDVF.
Effects of Azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation
Biochem Biophys Res Commun 2022 Apr 16;600:123-129.PMID:35219100DOI:10.1016/j.bbrc.2022.02.031.
Background: Proarrhythmic risk of conventional anti-arrhythmic agents is linked to unintended modulation of membrane voltage dynamics. We have demonstrated that the anti-fibrillatory effect of Azumolene is mediated via stabilization of the hyperphosphorylated ryanodine receptor (RyR2), leading to attenuation of diastolic calcium leak. However, the concomitant effects on membrane voltage dynamics have not been evaluated yet. Methods: After baseline optical mapping, Langendorff-perfused rabbit hearts treated with Azumolene, or vehicle, were subjected to global ischemia-reperfusion (I/R) followed by two episodes of long-duration ventricular fibrillation (LDVF). Simultaneous dual epicardial calcium transient (CaT) and voltage dynamics were studied optically. Results: Pre-treatment with Azumolene was associated with higher CaT amplitude alternans ratios (0.94 ± 0.02 vs. 0.78 ± 0.03 in control hearts, at 6 Hz; p = 0.005; and action potential amplitude alternans ratio (0.95 ± 0.02 vs. 0.78 ± 0.04 at 6.0 Hz; p = 0.02), and reduction of action potential duration (APD80) dispersion (9.0 ± 4.8 msec vs. 19.3 ± 6.6 msec at 6.0 Hz p = 0.02) and optical action potential upstroke rise time (26.3 ± 2.6 msec in control vs. 13.8 ± 0.6 msec at 6.0 Hz, p = 0.02) after LDVF. No change in action potential duration (APD) was noted with Azumolene treatment. Conclusion: In a model of ischemic recurrent LDVF, treatment with Azumolene led to reduction of cardiac alternans, i.e., calcium and voltage alternans. Unlike conventional anti-arrhythmic agents, reduction of action potential upstroke rise time and preservation of action potential duration following Azumolene treatment may reduce the proarrhythmia risk.
Azumolene reverses episodes of malignant hyperthermia in susceptible swine
Anesth Analg 1990 Mar;70(3):253-5.PMID:2305975DOI:10.1213/00000539-199003000-00004.
Azumolene is an analogue of dantrolene with much greater water solubility. Ten swine susceptible to malignant hyperthermia (MH) were triggered into MH episodes via the inhalation of halothane, and Azumolene was effective in terminating all of the MH episodes. There was an inverse relationship between the dose of Azumolene required to terminate the MH episode and the time it took for the pig to manifest the signs of MH. Azumolene was found to be similar in potency to dantrolene.
N-Acylhydrazones as drugs
Bioorg Med Chem Lett 2018 Sep 15;28(17):2797-2806.PMID:30006065DOI:10.1016/j.bmcl.2018.07.015.
Over the last two decades, N-acylhydrazone (NAH) has been proven to be a very versatile and promising motif in drug design and medicinal chemistry. Herein, we discuss the current and future challenges in the emergence of bioactive NAH-based scaffolds and to developing strategies to overcome the failures in drug discovery. The NAH-related approved drugs nitrofurazone, nitrofurantoin, carbazochrome, testosterone 17-enanthate 3-benzilic acid hydrazine, nifuroxazide, dantrolene, and Azumolene are already used as therapeutics in various countries. PAC-1 is an NAH-based therapeutic agent that entered clinical trials in 2015. Another NAH-derived scaffold, LASSBio-294, is in preclinical trials. This review highlights the detailed comprehensive assessment and therapeutic landscape of bioactive NAH motif scaffolds in preclinical and clinical studies published to date and their promise and associated challenges in current and future drug discovery of NAH-based drugs that will progress to clinical use.
Effects of Azumolene on normal and malignant hyperthermia-susceptible skeletal muscle
Basic Clin Pharmacol Toxicol 2008 Mar;102(3):308-16.PMID:18047479DOI:10.1111/j.1742-7843.2007.00156.x.
Malignant hyperthermia is a pharmacogenetic disease of skeletal muscle in which a life-threatening, hypermetabolic syndrome is induced by exposure of susceptible patients to halogenated general anaesthetics and/or succinylcholine. Dantrolene sodium, the only drug effective for treatment of malignant hyperthermia, has low water solubility that makes its clinical use difficult. The aim of this study was to investigate the potency of Azumolene, a 30-fold more water-soluble analogue, in comparison to the prototype dantrolene sodium, on mammalian and human skeletal muscles. The twitches of extensor digitorum longus and soleus muscles from mice were inhibited by Azumolene with IC(50) of 2.8 +/- 0.8 and 2.4 +/- 0.6 microM, respectively. The IC(50) of dantrolene sodium in these muscles was 1.6 +/- 0.4 and 3.5 +/- 1.2 microM, respectively, with no difference in comparison to Azumolene. Previous in vitro exposure of mouse soleus muscle to Azumolene and dantrolene sodium (10 microM) significantly inhibited 8 mM caffeine-induced contractures. Azumolene was just effective as dantrolene sodium in relaxing caffeine-induced contractures of mouse soleus muscle. Intravenous injection caused dose-dependent decreases in twitches of guinea pig gastrocnemius muscle with IC(50) of 1.2 +/- 0.1 and 1.5 +/- 0.2 mg/kg for Azumolene and dantrolene sodium, respectively. Azumolene, 10 microM, was effective in blocking and reversing caffeine-induced contracture of human malignant hyperthermia susceptible skeletal muscle in vitro. These studies provide evidence that Azumolene is equipotent to dantrolene sodium in blocking pharmacologic-induced muscle contractures and that Azumolene should be efficacious for treatment/prevention of malignant hyperthermia.