U-51605

Prostaglandin I2 synthase inhibitor 9α[2]

U-51605 (3 μM) 可抑制乙酰胆碱诱导的内皮依赖性收缩[1]。U-51605 (0.5、1、3、10 μM) 可增加乙酰胆碱诱导的 PGE2 和 PGF2α 释放[1]。U-51605同时抑制血栓素合成和血小板悬液聚集。

前列腺素IP受体拮抗剂4,5-二氢-N-[4-[[4-（1-甲基乙氧基）苯基]甲基]苯基]-1H-咪唑-2-胺（CAY10441）和前列腺素I2合酶抑制剂9α，11α-偶氮前列腺素-5Z，13E-二烯-1-酸（U-51605）对NOR3诱导的视网膜血管舒张反应显示出类似的预防作用。CAY10441和U-51605均未对NOR3的降压反应产生任何显著影响。NOR3增强了培养的人视网膜微血管内皮细胞释放前列腺素I2，环氧化酶-1抑制剂SC-560几乎完全消除了NOR3诱导的前列腺素I2释放，但环氧化酶-2抑制剂NS-398没有完全消除。然而，NOR3并没有增加人肠微血管内皮细胞释放前列腺素I2。这些结果表明，NO通过视网膜血管系统中的环氧化酶-1/前列腺素I2/前列腺素IP受体信号机制发挥其舒张作用[2]。

Stock solutions of U-51605 in methyl acetate (5 mg/ml) and CAY10441 in dimethyl sulfoxide (20 mg/ml) were diluted in saline, separately. The final concentrations of methyl acetate and dimethyl sulfoxide in these solutions were 12% and 45%, respectively. [2]
Indomethacin (5 mg/kg), U-51605 (0.6 mg/kg) or CAY10441 (6 mg/kg) was administered i.v., and the methoxamine infusion was started 45 min later (15 min for indomethacin). The timing of administration and dose of each compound were selected based on previous reports (Ogawa et al., 2007, Ogawa et al., 2009, Gohin et al., 2011). After hemodynamic parameters had reached a stable level (~15 min later), NOR3 (0.5–10 μg/kg/min) or prostaglandin I2 (0.005–0.3 μg/kg/min) was injected into the femoral vein, using a syringe pump. [2]

[1]. Thromboxane synthetase inhibitors as pharmacological tools: differential biochemical and biological effects on platelet suspensionsJ. Prostaglandins, 1977, 14(5): 897-907.

[2]. Involvement of prostaglandin I2 in nitric oxide-induced vasodilation of retinal arterioles in ratsJ. European Journal of Pharmacology, 2015, 764: 249-255.

The comparative effects of three so called “thromboxane-synthetase- inhibitors” (imisazole, N-0.164, and U-51065) on arachidonate metabolism and on platelet aggregation were studied. All three compounds blocked platelet microsomal thromboxane synthesis from prostaglandin endoperoxides without affecting platelet adenyl cyclase. Imidazole, blocked thromboxane synthesis in intact platelets either from arachidonic acid or PGH2, without affecting aggregation. U-51605 simultaneously inhibited thromboxane synthesis and platelet suspension aggregation. N-0164 inhibited aggregation probably at extracellular sites, at concentrations that did not alter arachidonate or PGH2 metabolism. High concentrations of N-0164 simultaneously inhibited PG cyclo-oxygenase and thromboxane synthetase. The lack of specificity of these compounds requires that other actions of these compound must be considered when they are used as pharmacological tools to inhibit thromboxane synthetase. [2]

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The soluble guanylyl cyclase/cGMP system plays an important role in the vasodilator response to nitric oxide (NO) in various vascular beds. However, in rat retinal arterioles, the cyclooxygenase-1/cAMP-mediated pathway contributes to the vasodilator effects of NO, although the specific prostanoid involved remains to be elucidated. In the present study, we investigated the role of prostaglandin I2 and its receptor (prostanoid IP receptor) system in NO-induced vasodilation of rat retinal arterioles in vivo. Fundus images were captured using a digital camera that was equipped with a special objective lens. Changes in diameter of retinal arterioles were assessed. The NO donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) increased the diameter of retinal arterioles but decreased systemic blood pressure in a dose-dependent manner. Treatment of rats with indomethacin, a non-selective cyclooxygenase inhibitor, markedly attenuated the retinal vasodilator, but not depressor responses to NOR3. The prostanoid IP receptor antagonist 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine (CAY10441), and the prostaglandin I2 synthase inhibitor 9α,11α-azoprosta-5Z,13E-dien-1-oic acid (U-51605), both showed similar preventive effects against the NOR3-induced retinal vasodilator response. Neither CAY10441 nor U-51605 showed any significant effects on the depressor response to NOR3. NOR3 enhanced the release of prostaglandin I2 from cultured human retinal microvascular endothelial cells and the NOR3-induced prostaglandin I2 release was almost completely abolished by the cyclooxygenase-1 inhibitor SC-560, but not by the cyclooxygenase-2 inhibitor NS-398. However, NOR3 did not increase the release of prostaglandin I2 from human intestinal microvascular endothelial cells. These results suggest that NO exerts its dilatory effect via cyclooxygenase-1/prostaglandin I2/prostanoid IP receptor signaling mechanisms in the retinal vasculature. [2]

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In the present study, we used U-51605 as an inhibitor of prostaglandin I2 synthase. However, the compound can inhibit thromboxane synthase (Gorman et al., 1977) and act on prostanoid TP receptors as a partial agonist (Gluais et al., 2005). The results clearly indicated that U-51605 reduced the NOR3-induced vasodilation of retinal arterioles to a similar degree as the prostanoid IP receptor antagonist CAY10441. However, we cannot exclude the possibility that effects of U-51605 on the thromboxane A2/prostanoid TP receptor system could also contribute to its inhibitory effect on NOR3-induced responses. Unfortunately, selective inhibitors for prostaglandin I2 synthase are not currently available. In the future, when highly selective inhibitors for this enzyme are developed, these issues should be addressed. In conclusion, inhibitors of cyclooxygenase and prostaglandin I2 synthase, as well as antagonists of prostanoid IP receptors, markedly reduced NOR3-induced vasodilation of rat retinal arterioles. Therefore, in response to NO, cyclooxygenase is most likely to provide the substrate for prostaglandin I2 synthase, which catalyzes the conversion of prostaglandin H synthase 2 to prostaglandin I2, the potent vasodilator. Prostaglandin I2, in turn, stimulates prostanoid IP receptors, leading to vasodilation of retinal arterioles in rats. The cyclooxygenase/prostaglandin I2/prostanoid IP receptor/cAMP signaling pathway appears to play an important role in the regulation of retinal blood flow. Therefore, the interaction between NO and the cyclooxygenase-dependent pathway may have a role in regulating retinal hemodynamics under physiological conditions. However, the role of this interaction in the pathogenesis of retinal diseases such as diabetic retinopathy and glaucoma remains to be elucidated. These issues should be addressed in future studies.[2]

C20H32N2O2

332.48

64192-56-9

Typically exists as solids at room temperature

C(O)(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/CCCCCC)[C@@]2([H])C[C@]1([H])N=N2

9,11-Azoprosta-5,13-dienoic acid; U 51605; 64192-56-9; (Z)-7-[(1R,4S,5R)-1-[(E)-Oct-6-enyl]-2,3-diazabicyclo[2.2.1]hept-2-en-5-yl]hept-5-enoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。