MRS2690

P2Y14 receptor

目的：UDP糖可以作为细胞外信号分子，但对其心血管作用知之甚少。P2Y14受体是一种Gi/o偶联受体，由UDP葡萄糖和相关糖核苷酸激活。在这项研究中，我们试图使用选择性P2Y14受体激动剂MRS2690和新型选择性P2Y114受体拮抗剂PPTN（4,7-二取代萘甲酸衍生物）来研究P2Y14接收器是否在猪冠状动脉中功能性表达。 方法和结果：采用等轴测张力记录来评估UDP糖对猪离体冠状动脉段的影响。研究了P2受体拮抗剂苏拉明和PPADS、P2Y14受体拮抗剂PPTN和P2Y6受体拮抗剂MRS2578的作用。使用流式细胞术测量血管舒张剂刺激的磷蛋白（VASP）磷酸化，以评估cAMP水平的变化。UDP-葡萄糖、UDP-葡萄糖醛酸UDP-N-乙酰葡糖胺（P2Y14受体激动剂）引发猪冠状动脉的浓度依赖性收缩。MRS2690是一种比UDP糖更有效的血管收缩剂。在毛喉素（cAMP激活剂）存在的情况下，对MRS2690和UDP糖的浓度依赖性收缩反应增强，其中通过添加血栓烷A2模拟物U46619来维持基础张力水平。对MRS2690的收缩反应被PPTN阻断，但未被MRS2578阻断。PPTN和苏拉明也减弱了对UDP葡萄糖的收缩反应，但MRS2578没有。在暴露于UDP葡萄糖和MRS2690的猪冠状动脉中，毛喉素诱导的VASP磷酸化减少，这与P2Y14受体与Gi/o蛋白的偶联和腺苷酸环化酶活性的抑制一致。 结论：我们的数据支持UDP糖作为细胞外信号分子的作用，并首次表明它们通过P2Y14受体介导猪冠状动脉的收缩[1]。

[1]. UDP-sugars activate P2Y14 receptors to mediate vasoconstriction of the porcine coronary artery. Vascul Pharmacol. 2018 Apr:103-105:36-46.

Background: Enterochromaffin cells (ECs) synthesize and release serotonin (5-HT) and adenosine triphosphate (ATP) to trigger or regulate enteroneurinic reflexes and transmit visceral/pain sensory information. Alterations in the 5-HT signaling pathway may be involved in the pathogenesis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), but the pharmacological or molecular mechanisms regulating Ca2+-dependent 5-HT release remain unclear. Previous studies have shown that purinergic signaling via ATP and ADP is an important mechanism regulating 5-HT release. However, ECs also respond to uridine triphosphate (UTP) and uridine diphosphate (UDP), suggesting that uridine triphosphate receptors and signaling pathways are also involved. We tested the hypothesis that UTP is a regulator of 5-HT release in human ECs. Methods: We investigated the UTP signaling pathway mechanism in human EC model BON cells using Fluo-4/Ca2+ imaging, patch-clamp, pharmacological analysis, immunohistochemistry, Western blotting, and qPCR. The release of serotonin (5-HT) was monitored in enteric ganglion cells (hECs) or osteochondral cells (BONs) isolated from human intestinal surgical specimens. Results: UTP, UTPγS, UDP, and ATP all induced Ca2+ oscillations in BONs. UTP induced a concentration-dependent biphasic Ca2+ response. The cellular response order was: UTP, ATP > UTPγS > UDP >> MRS2768, BzATP, α,β-MeATP > MRS2365, MRS2690, and NF546. Cells activated by UTP and ATP at varying proportions also responded to UTPγS (P2Y4, 50% of cells), UDP (P2Y6, 30%), UTPγS and UDP (14%), or MRS2768 (<3%). UTP-induced Ca2+ responses could be blocked by PLC, IP3R, SERCA Ca2+ pumps, inhibitors of La3+-sensitive Ca2+ channels, or BAPTA/AM chelation of intracellular free Ca2+. Inhibitors of L-type calcium channels, TRPC, raneidin-Ca2+ pools, PI3 kinase, PKC, or SRC kinases had no such effect. UTP stimulated depolarization of voltage-sensitive Ca2+ current (ICa) and membrane potential (Vm), and inhibited IK current (but not IA current). The IKv7.2/7.3 K+ channel blocker XE-991 mimicked UTP-induced Vm depolarization and blocked the UTP response. XE-991 blocks IK currents, while UTP further reduces them. La3+ or PLC inhibitors block UTP-induced depolarization; PKC inhibitors, thapsigargin, or zero Ca2+ buffer have no such effect. UTP stimulates the release of 5-HT from hEC cells expressing TPH1, 5-HT, and P2Y4/P2Y6R. Zero Ca2+ buffer enhances Ca2+ response and 5-HT release. Conclusion: UTP activates the major P2Y4R pathway, mobilizing intracellular Ca2+ via the PLC/IP3/IP3R/SERCA Ca2+ signaling pathway, thereby triggering Ca2+ oscillations and stimulating 5-HT release; Ca2+ influx is inhibitory. UTP-induced membrane potential depolarization depends on the PLC signaling pathway and an unidentified K channel (which appears to be independent of Ca2+ oscillations or Ica/VOCC). A UTP-gated signaling pathway triggered by P2Y4R activation stimulates 5-HT release. Front Pharmacol. 2017 Jul 13:8:429.

C15H22N2NA2O16P2S

626.32

625.996

C, 28.77; H, 3.54; N, 4.47; Na, 7.34; O, 40.87; P, 9.89; S, 5.12

15039-58-4

73755042

Typically exists as solid at room temperature

312

7

17

9

38

981

9

[Na+].[Na+].OC[C@H]1O[C@H](OP(OP(OC[C@H]2O[C@@H](N3C=CC(=O)NC3=S)[C@H](O)[C@@H]2O)(=O)[O-])(=O)[O-])[C@H](O)[C@@H](O)[C@@H]1O

TYVFMVSNSGMZPA-QBNUFUENSA-L

InChI=1S/C15H24N2O16P2S.2Na/c18-3-5-8(20)10(22)12(24)14(31-5)32-35(27,28)33-34(25,26)29-4-6-9(21)11(23)13(30-6)17-2-1-7(19)16-15(17)36;;/h1-2,5-6,8-14,18,20-24H,3-4H2,(H,25,26)(H,27,28)(H,16,19,36);;/q;2*+1/p-2/t5-,6-,8-,9-,10+,11-,12-,13-,14-;;/m1../s1

disodium;[[(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-oxo-2-sulfanylidenepyrimidin-1-yl)oxolan-2-yl]methoxy-oxidophosphoryl] [(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate

MRS 2690; MRS-2690; MRS2690; MRS 2690; MRS-2690; 15039-58-4; GTPL3337; GLXC-04134; [[[(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-oxo-2-sulfanylidenepyrimidin-1-yl)oxolan-2-yl]methoxy-sodiooxyphosphoryl]oxy-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphosphoryl]oxysodium; MRS 2690; DIPHOSPHORIC ACID 1-A-D-GLUCOPYRANOSYL ESTER 2-[(4'-METHYLTHIO)URIDIN-5''-YL] ESTER DISODIUM SALT; MRS2690

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。