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AUY954

目录号 : GC42877

A selective S1P1 receptor agonist

AUY954 Chemical Structure

Cas No.:820240-77-5

规格 价格 库存 购买数量
500μg
¥839.00
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1mg
¥1,593.00
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5mg
¥5,037.00
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产品描述

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.

Chemical Properties

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
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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
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Research Update

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.