ARN726
目录号 : GC45386An NAAA inhibitor
Cas No.:1628343-77-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ARN726 is an inhibitor of N-acylethanolamine acid amidase (NAAA; IC50s = 27 and 63 nM for the human and rat enzyme, respectively).1 It is selective for NAAA over fatty acid amide hydrolase (FAAH) and acid ceramidase (IC50s = >100 and 12.5 μM, respectively), as well as a panel of 28 lipid metabolism- and inflammation-related enzymes at 10 μM. ARN726 (1-30 mg/kg) decreases lung myeloperoxidase activity and pleural exudate TNF-α levels in a mouse model of carrageenan-induced lung inflammation. It inhibits NAAA and reverses complete Freund's adjuvant-induced decreases in palmitoyl ethanolamide and oleoyl ethanolamide levels in inflamed paw tissue in a rat model of arthritis.2
References
1. Ribeiro, A., Pontis, S., Mengatto, L., et al. . Chem. Biol. 10, 1838-1846 (2015).
2. Bonezzi, F.T., Sasso, O., Pontis, S., et al. An important role for N-acylethanolamine acid amidase in the complete Freund's adjuvant rat model of arthritis. J. Pharmacol. Exp. Ther. 356(3), 656-663 (2016).
| Cas No. | 1628343-77-0 | SDF | |
| 化学名 | N-[(3S)-2-oxo-3-azetidinyl]-carbamic acid, 4-cyclohexylbutyl ester | ||
| Canonical SMILES | O=C(N[C@H]1CNC1=O)OCCCCC2CCCCC2 | ||
| 分子式 | C14H24N2O3 | 分子量 | 268.4 |
| 溶解度 | DMF: 33 mg/ml,DMSO: 33 mg/ml,Ethanol: 33 mg/ml,Ethanol:PBS (pH 7.2) (1:4): 0.20 mg/ml | 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 | 3.7258 mL | 18.6289 mL | 37.2578 mL |
| 5 mM | 0.7452 mL | 3.7258 mL | 7.4516 mL |
| 10 mM | 0.3726 mL | 1.8629 mL | 3.7258 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。
Activity-Based Probe for N-Acylethanolamine Acid Amidase
ACS Chem Biol 2015 Sep 18;10(9):2057-2064.PMID:26102511DOI:10.1021/acschembio.5b00197.
N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid signaling molecules that includes oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Among the reported NAAA inhibitors, α-amino-β-lactone (3-aminooxetan-2-one) derivatives have been shown to prevent FAE hydrolysis in innate-immune and neural cells and to reduce reactions to inflammatory stimuli. Recently, we disclosed two potent and selective NAAA inhibitors, the compounds ARN077 (5-phenylpentyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate) and ARN726 (4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate). The former is active in vivo by topical administration in rodent models of hyperalgesia and allodynia, while the latter exerts systemic anti-inflammatory effects in mouse models of lung inflammation. In the present study, we designed and validated a derivative of ARN726 as the first activity-based protein profiling (ABPP) probe for the in vivo detection of NAAA. The newly synthesized molecule 1 is an effective in vitro and in vivo click-chemistry activity based probe (ABP), which is able to capture the catalytically active form of NAAA in Human Embryonic Kidney 293 (HEK293) cells overexpressing human NAAA as well as in rat lung tissue. Competitive ABPP with 1 confirmed that ARN726 and ARN077 inhibit NAAA in vitro and in vivo. Compound 1 is a useful new tool to identify activated NAAA both in vitro and in vivo and to investigate the physiological and pathological roles of this enzyme.
N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-preferring rats
Psychopharmacology (Berl) 2021 Jan;238(1):249-258.PMID:33037452DOI:10.1007/s00213-020-05678-7.
Rationale: N-acylethanolamine acid amidase (NAAA) is an intracellular cysteine hydrolase that terminates the biological actions of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), two endogenous lipid-derived agonists of the nuclear receptor, and peroxisome proliferator-activated receptor-α. OEA and PEA are important regulators of energy balance, pain, and inflammation, but recent evidence suggests that they might also contribute to the control of reward-related behaviors. Objectives and methods: In the present study, we investigated the effects of systemic and intracerebral NAAA inhibition in the two-bottle choice model of voluntary alcohol drinking and on operant alcohol self-administration. Results: Intraperitoneal injections of the systemically active NAAA inhibitor ARN19702 (3 and 10 mg/kg) lowered voluntary alcohol intake in a dose-dependent manner, achieving ≈ 47% reduction at the 10 mg/kg dose (p < 0.001). Water, food, or saccharin consumption was not affected by the inhibitor. Similarly, ARN19702 dose-dependently attenuated alcohol self-administration under both fixed ratio 1 (FR-1) and progressive ratio schedules of reinforcement. Furthermore, microinjection of ARN19702 (1, 3 and 10 μg/μl) or of two chemically different NAAA inhibitors, ARN077 and ARN726 (both at 3 and 10 μg/μl), into the midbrain ventral tegmental area produced dose-dependent decreases in alcohol self-administration under FR-1 schedule. Microinjection of ARN19702 into the nucleus accumbens had no such effect. Conclusion: Collectively, the results point to NAAA as a possible molecular target for the treatment of alcohol use disorder.
An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freund's Adjuvant Rat Model of Arthritis
J Pharmacol Exp Ther 2016 Mar;356(3):656-63.PMID:26769918DOI:10.1124/jpet.115.230516.
The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-α. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. Injection of CFA into the paw produced local edema and heat hyperalgesia, which were accompanied by decreased PEA and OEA content (assessed by liquid chromatography/mass spectrometry) and increased NAAA levels (assessed by Western blot and ex vivo enzyme activity measurements) in paw tissue. Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFA-induced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis.