AUY954
目录号 : GC42877A selective S1P1 receptor agonist
Cas No.:820240-77-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AUY954 is an orally bioavailable and selective agonist of the sphingosine-1-phosphate receptor 1 (S1P1; EC50 = 1.2 nM for stimulating GTPγS binding to S1P1 in CHO cells). It is highly selective for the S1P1 receptor with EC50 values of >10,000, 1,210, >1,000, and 340 nM for S1P2, S1P3, S1P4, and S1P5 receptors, respectively. AUY954 reduces circulating lymphocytes and prevents rejection of rat heart allografts. In a rat model of experimental autoimmune neuritis, chronic treatment with AUY954 (10 mg/kg), starting on the day of immunization, almost completely prevents peripheral paralysis. In the same model, it also decreases T cell, B cell, and macrophage infiltration and perivascular demyelination in sciatic nerves.
| Cas No. | 820240-77-5 | SDF | |
| Canonical SMILES | OC(CCNCC1=CC=C2C(C=C(C3=CC(C(F)(F)F)=C(C4=CC=CC=C4)C=C3)S2)=C1)=O | ||
| 分子式 | C25H20F3NO2S | 分子量 | 455.5 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,DMSO:PBS (pH 7.2) (1:1): 0.5 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 | 2.1954 mL | 10.9769 mL | 21.9539 mL |
| 5 mM | 0.4391 mL | 2.1954 mL | 4.3908 mL |
| 10 mM | 0.2195 mL | 1.0977 mL | 2.1954 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。
AUY954, a selective S1P(1) modulator, prevents experimental autoimmune neuritis
J Neuroimmunol 2009 Nov 30;216(1-2):59-65.PMID:19804913DOI:10.1016/j.jneuroim.2009.09.010.
Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and an animal model of human inflammatory demyelinating polyradiculoneuropathy. AUY954, which targets selectively the sphingosine-1-phosphate receptor 1 (S1P(1)), is known to sequester lymphocytes into secondary lymphoid tissues. In EAN rats, AUY954 greatly prevented paraparesis if administrated from the day of immunization. T cell, B cell, and macrophage infiltration, inflammatory demyelination, and local expression of interleukine-17 and matrix metalloproteinase-9 in sciatic nerves of EAN rats were significantly decreased by AUY954 treatment. Therefore, S1P(1) modulation might be a potential treatment option for inflammatory neuropathies.
S1P1 Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia
Biomol Ther (Seoul) 2019 Nov 1;27(6):522-529.PMID:31181588DOI:10.4062/biomolther.2019.005.
M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 (S1P1) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P1 and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P1 is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P1 was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P1 activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P1 activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P1 in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P1 activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P1 could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P1 activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P1 activation. Overall, these results revealed S1P1-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.
Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3
Biochem Biophys Res Commun 2016 Aug 5;476(4):627-634.PMID:27282481DOI:10.1016/j.bbrc.2016.06.009.
Endothelial nitric oxide synthase (eNOS) plays a crucial role in vascular homeostasis. Lysophospholipid interaction with sphingosine 1-phosphat (S1P) receptors results in eNOS activation in different cells. In endothelial cells, eNOS activation via S1P1 or S1P3 was shown controversially. The aim of this study is to investigate the meaning of both S1P receptors for eNOS activation in human endothelial cells. Therefore, several S1P1 and S1P3 agonists in combination with antagonists and specific RNAi approach were used. eNOS activation was measured in human umbilical vein endothelial cells (HUVEC) via DAF2-DA-based fluorescence microscopy. For investigation of the signaling pathway, agonists/antagonist studies, RNAi approach, Luminex™ multiplex, and Western Blot were used. In HUVEC, both the S1P1 agonist AUY954 as well as the S1P1,3 agonist FTY720P induced eNOS activation in a time- and dose-dependent manner. Other S1P1 agonists activated eNOS to a lesser extent. The AUY954-induced eNOS activation was blocked by the S1P1 antagonist W146, the combination of W146 and the S1P3 antagonist CAY10444 and the S1P1,3 antagonist VPC23019, but not by CAY10444 indicating the meaning of S1P1 for the AUY954-induced eNOS activation. The FTY720P-induced eNOS activation was blocked only by the combination of W146 and CAY10444 and the combined S1P1,3 antagonist VPC23019, but not by W146 or CAY10444 indicating the importance of both S1P1 and S1P3 for FTY720-induced eNOS activation. These results were confirmed using specific siRNA against S1P1 and S1P3. The S1P1,3 activation results in Akt phosphorylation and subsequent activation of eNOS via phosphorylation at serine(1177) and dephosphorylation at threonine(495). Beside former investigations with rather unspecific S1P receptor activation these data show potent selective S1P1 activation by using AUY954 and with selective S1P receptor inhibition evidence was provided that both S1P1 and S1P3 lead to downstream activation of eNOS in HUVEC in the same experimental setting. Inhibition or knockdown of one of these receptor subtypes did not abolish the eNOS activation and subsequent NO production.
Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis
Cells 2020 May 22;9(5):1290.PMID:32455907DOI:10.3390/cells9051290.
Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both "immunological" and "non-immunological" actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy.
Sphingosine-1-phosphate-induced airway hyper-reactivity in rodents is mediated by the sphingosine-1-phosphate type 3 receptor
J Pharmacol Exp Ther 2012 Aug;342(2):399-406.PMID:22570366DOI:10.1124/jpet.112.191585.
There is a need to better understand the mechanism of airway hyper-reactivity, a key feature of asthma. Evidence suggests that sphingosine-1-phosphate (S1P) could be a major player in this phenomenon. The purpose of this work was to define the S1P receptor responsible for this phenomenon. We have studied, in the rat, the effect of two S1P synthetic receptor ligands, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) (which in its phosphorylated form is a potent agonist at each S1P receptor except S1P(2)) and 3-[[2-[4-phenyl-3-(trifluoromethyl)phenyl]-1-benzothiophen-5-yl]methylamino]propanoic acid (AUY954) (a selective S1P(1) agonist) on lung function in vivo. This was complemented by in vitro studies using isolated trachea from the rat, the S1P(3) receptor-deficient mouse, and its wild-type counterpart. After oral administration, FTY720 induced a generalized airway hyper-reactivity to a range of contractile stimuli. This was observed as early as 1 h postdosing, lasted for at least 24 h, and was not subject to desensitization. In both rat and wild-type mouse isolated trachea, preincubation with the active phosphorylated metabolite of FTY720 induced hyper-responsiveness to 5-hydroxytryptamine. This effect was not seen in the isolated tracheas from S1P(3) receptor-deficient mice. AUY954, did not mimic the effect of FTY720 either in vivo or in vitro. Our data are consistent with activation of the S1P pathway inducing a generalized airway hyper-reactivity in rats and mice that is mediated by the S1P(3) receptor. S1P(3) receptor antagonists might prove to be useful as new therapeutic strategies aimed at blocking the airway hyper-reactivity observed in asthma.