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AM1241

现货
Catalog No.
A5827
大麻素CB2受体激动剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,000.00
现货
5mg
¥ 450.00
现货
10mg
¥ 850.00
现货
25mg
¥ 1,900.00
现货

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Background

IC50: AM-1241 is a selective cannabinoid CB2 receptor agonist with Ki of 3.4 nM, exhibits 82-fold selectivity over CB1 receptor. [1].
The cannabinoid receptor type 2, abbreviated as CB2, is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. CB2 receptors may have possible therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease. AM-1241, a chemical from the aminoalkylindole family, acts as a potent and selective agonist for the cannabinoid receptor CB2, has analgesic effects in animal studies, particularly against "atypical" pain such as hyperalgesia and allodynia.
In vitro: The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo. In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB2, but an inverse agonist at rat and mouse CB2 receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB2 receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB2 receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB2 receptors. These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB2 receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB2 agonist enantiomer of AM1241, is consistent with previous observations that CB2 agonists are effective in relief of pain [2].
In vivo:
Effective treatment or amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1G93A transgenic mice). Administration at the onset of tremors delayed motor impairment in treated mice when compared to vehicle controls. Three conditions of ALS, the loss of motor function, paralysis scoring and weight loss, were analyzed using a mathematical model. Loss of motor function (as assessed by performance on a rotarod) was delayed by 12.5 days in male mice by AM1241. In female mice, AM1241 extended rotarod performance by 3 days, although this was not statistically significant. In male mice, AM1241 also extended by 5 days the time to reach the 50%point on a visually-assessed performance scale.AM1241 did not affectweight loss or survival (129.8±1.7 days, vehicle; 129.1±7.0 days, AM1241, n=16). As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases [3].
Clinical trial: AM1241 is still in preclinical development phase and no clinical study has been found.
Reference:
[1] Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F, Makriyannis A, Malan TP Jr. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003;100(18):10529-33.
[2] B Bingham, PG Jones, AJ Uveges, S Kotnis, P Lu, VA Smith, S-C Sun, L Resnick, M Chlenov, Y He. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. British Journal of Pharmacology (2007) 151, 1061–1070
[3] Kathline Kim, Dan H. Moore, Alexandros Makriyannis, Mary E. Abood. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. European Journal of Pharmacology 542 (2006) 100-105

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt503.33
Cas No.444912-48-5
FormulaC22H22IN3O3
Solubility≥50.3mg/mL in DMSO with gentle warming, ≥3.87 mg/mL in EtOH with ultrasonic, <2.57 mg/mL in H2O
Chemical Name(2-iodo-5-nitrophenyl)-[1-[(1-methylpiperidin-2-yl)methyl]indol-3-yl]methanone
SDFDownload SDF
Canonical SMILESCN1CCCCC1CN2C=C(C3=CC=CC=C32)C(=O)C4=C(C=CC(=C4)[N+](=O)[O-])I
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

结合实验

从稳定表达人CB2受体的HEK细胞或稳定表达人CB1受体的CHO细胞系制备膜样品。在蛋白酶抑制剂存在下,在含有50 mM Tris-HCl、pH 7.4、1 mM MgCl2和1 mM EDTA的缓冲液中,使用Polytron进行2×10秒脉冲,收获细胞并匀化,然后以45000g离心20分钟将膜沉淀物以-80℃等份洗涤并冷冻。在含有50 mM Tris-HCl、pH 7.4、2.5 mM EDTA、5 mM MgCl2和0.05%无脂肪酸牛血清白蛋白(BSA)的测定缓冲液中,使用[3H]CP 55,940(0.01-8 nm)在30℃下进行饱和结合反应90分钟,通过UniFilter-96 GF/C过滤板快速真空过滤终止反应,并用冷测定缓冲液洗涤四次。在测试化合物(0.1 nM-10μM)存在下,使用0.5 nM [3H] CP 55,940进行竞争实验。非特异性结合由10μM未标记的CP 55,940定义。

细胞实验 [1]:

细胞系

稳定表达人CB2受体的人胚肾(HEK)细胞,稳定表达人CB1受体的中国仓鼠卵巢(CHO)细胞系

溶解方法

该化合物在DMSO中的溶解度大于25.2 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

Ki:~7 nM (人CB2受体)

应用

在稳定表达人CB2受体的HEK细胞中,AM1241表现出拮抗活性,以浓度依赖性方式阻断激动剂CP 55,940-诱发的Ca2+应答,Kb值为63 nM。在分别表达重组人CB2和CB1受体的稳定的HEK和CHO细胞系膜上,在[3H] CP 55,940竞争结合测定中,AM-1241在人CB2受体上表现出高亲和力,Ki值为约7 nM,而其在人CB1受体上的亲和力较弱,超过80倍。

动物实验 [2]:

动物模型

成年雄性Sprague-Dawley大鼠

给药剂量

腹腔注射,100或330 μg/kg

应用

AM1241(100、330 μg/kg,i.p.)抑制角叉菜胶诱发的热和机械痛觉过敏以及异常性疼痛的发展。在给予角叉菜胶注射的爪中足底注射AM1241(33 μg/kg)抑制了痛觉过敏和异常性疼痛,但在对侧(非发炎)爪施用后却无活性。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Yao B B, Mukherjee S, Fan Y, et al. In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor[J]. British journal of pharmacology, 2006, 149(2): 145-154.

[2]. Nackley A G, Makriyannis A, Hohmann A G. Selective activation of cannabinoid CB 2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation[J]. Neuroscience, 2003, 119(3): 747-757.

生物活性

描述 AM-1241是大麻素CB2受体的选择性激动剂,Ki值为3.4 nM。
靶点 CB2 CB1        
IC50 3.4 nM(Ki) 280 nM(Ki)        

质量控制

质量控制和MSDS

批次:

化学结构

AM1241