更新于：2024-11-01

TBXA2R x PGI2 receptor

更新于：2024-11-01

基本信息

关联

项与 TBXA2R x PGI2 receptor 相关的药物

TRA-418

靶点

PGI2 receptor x TBXA2R

作用机制

PGI2 receptor激动剂 [+1]

在研机构-

原研机构

Hamamatsu University School of Medicine

在研适应症-

非在研适应症

脑卒中 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TBXA2R x PGI2 receptor 相关的临床结果

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100 项与 TBXA2R x PGI2 receptor 相关的转化医学

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0 项与 TBXA2R x PGI2 receptor 相关的专利（医药）

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项与 TBXA2R x PGI2 receptor 相关的文献（医药）

2020-12-01·Journal of Translational Medicine2区 · 医学

Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation

2区 · 医学

ArticleOA

作者: Misawa, Kiyoshi ; Kita, Junya ; Misawa, Yuki ; Endo, Shiori ; Imai, Atsushi ; Mima, Masato ; Mochizuki, Daiki ; Satoshi, Yamada ; Mineta, Hiroyuki ; Ishikawa, Ryuji ; Yamaguchi, Yuki

AbstractBackgroundChronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC.MethodsMethylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival.ResultsThe mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5–9 methylated genes had a significantly lower survival rate than that of patients with 0–4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5–9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively).ConclusionWe characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.

2020-04-01·Molecular Pharmacology3区 · 医学

Voltage Dependence of Prostanoid Receptors

3区 · 医学

Article

作者: Kurz, Michael ; Bünemann, Moritz ; Krett, Anna-Lena

G protein-coupled receptors (GPCRs) are the largest class of transmembrane receptors and serve as signal mediators to transduce information from extracellular signals such as neurotransmitters, hormones, or drugs to cellular responses. They are exposed to the strong electrical field of the plasma membrane. In the last decade voltage modulation of ligand-induced GPCR activity has been reported for several GPCRs. Using Foerster resonance energy transfer-based biosensors in patch clamp experiments, we discovered a robust voltage dependence of the thromboxane receptor (TP receptor) on the receptor level as well as on downstream signaling. TP receptor activity doubled upon depolarization from -90 to +60 mV in the presence of U46619, a stable analog of prostaglandin H₂ Half-maximal effective potential (V_0.5) determined for TP receptor was -46 mV, which is within the physiologic range. We identified that depolarization affected the agonist affinity for the TP receptor. Depolarization enhanced responses of several structural analogs of U46619 with modifications to a similar extent all around the molecule, indicating that voltage modulates the general conformation of TP receptor. By means of site direct mutagenesis, we identified TP receptor R295^7.40, which showed alteration of voltage sensitivity of TP receptor upon mutation. Voltage sensitivity was not limited to TP receptor because prostaglandin F receptor activated with U46619 and prostaglandin E₂ receptor subtype 3 activated with iloprost showed a similar reaction to depolarization as TP receptor. However, prostacyclin receptor activated with iloprost showed no detectable voltage dependence. SIGNIFICANCE STATEMENT: Prostanoids mediate many of their physiological effects via transmembrane receptors expressed in the plasma membrane of excitable cells. We found that agonist-mediated activation of prostaglandin F receptors and prostaglandin E₂ receptors as well as thromboxane receptors are activated upon depolarization, whereas prostacyclin receptors are not. The voltage-induced modulation of thromboxane receptor activity was observed on the level of receptor conformation and downstream signaling. The range of voltage dependence was restricted by R295^7.40 in the agonist-binding pocket.

2019-09-01·Thrombosis and Haemostasis2区 · 医学

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

2区 · 医学

Article

作者: Fu, Sidney W. ; Liu, Wen Wen ; Liu, Mei Lin ; Wang, Hao ; Chen, Xia Huan

AbstractAspirin has been widely used for the prevention of cardiovascular diseases, but its antiplatelet efficiency varies between individuals. The present study aimed to evaluate response to aspirin based on gene profiles as well as potential regulating pathways using human blood samples and cell lines. Platelet function in patients 50 years or older with coronary artery disease on 100 mg/day aspirin was measured by light transmission aggregometry (LTA) of arachidonic acid (AA)-induced platelet aggregation. The expression of eight candidate genes—PTGS1/COX1, PLA2G4A, PLA2G6, PLA2G7, TBXAS1, TBXA2R, PTGIR, and ITGA2B—and the ingredients involved in AA metabolism were analyzed. Our data showed that the expressions of thromboxane A synthase 1 (TBXAS1), thromboxane synthase (TXS), and thromboxane B2 (TXB2) were increased in the upper quartile of platelet aggregation (LTA-AA_Q4) group compared with the lower quartile of platelet aggregation (LTA-AA_Q1) group. Our bioinformatics analysis suggested that TBXAS1 was targeted by miR-34b-3p via binding to its 3′-UTR, which was subsequently verified experimentally. Although overexpression of miR-34b-3p exhibited no apparent effect on cell proliferation, inhibition of miR-34b-3p promoted megakaryocyte viability. Our data demonstrated that the expression of TBXAS1 was higher in the aspirin hyporesponsiveness group than that in the hyperresponsiveness group, suggesting that high expression of TBXAS1 may be associated with aspirin hyporesponsiveness. miR-34b-3p may regulate the platelet and aspirin response by suppressing TBXAS1 expression and megakaryocyte proliferation.

项与 TBXA2R x PGI2 receptor 相关的新闻（医药）

2022-07-05

·药融云

浴火历练14年！国家1类新药：艾瑞昔布

传统的非甾体抗炎药，其如影随行的胃肠道副作用一直是药学家的梦魇，但在二十世纪九十年代末，国外科学家率先发现这类药物的靶标环氧合酶（COX）存在两种同工酶——COX-1和COX-2。科学家们欣喜若狂，因为理论上高选择性COX-2抑制剂，将打破这一魔咒。随后研究者针对COX-1和COX-2在功能上的差别，研发了塞来昔布、罗非昔布等一系列非甾体抗炎药（COX-2选择抑制剂，图1）。经过数年的临床验证，表明这些选择COX-2抑制剂在疗效及胃肠道不良反应方面优于传统的非甾体抗炎药。但药物发现之路从来不是坦途。研究者在药物上市后的数年再次受创。二十世纪末，美国食品药品监督管理局批准MERCK公司的罗非昔布上市，但在这短短五年后，通过研究发现该药可产生心梗和卒中等心血管不良反应，于是该公司宣布在全球内撤回该药[1]。随后伐地考昔也被美国FDA勒令撤出市场，还要求修改塞来昔布的说明书，强调其心血管不良反应的风险。 “山重水复疑无路，柳暗花明又一村。”我们国家的科研人员，在自身技术稍落后但时代仍在推进的情况下，刻苦钻研，成功研发出一款高效低毒的国产新药——艾瑞昔布。中文名：艾瑞昔布（恒扬）[2]英文名称：ImrecoxibCAS号：395683-14-4分子式：C21H23NO3S结构式：见图2。研发公司：江苏恒瑞医药化合物专利：ZL00105899.1（2001年10月24日）上市时间：2011年6月8日适应症：有效缓解关节炎等疼痛症状比如膝骨处、脊柱处。作用机制：COX-2为主要抑制靶标，炎性前列腺素的产生从而抑制，减少炎症。同时，也会较少地抑制COX-1，因此很少影响人体生理正常保护的功能。剂型与规格：片剂，0.1g。不良反应：上腹不适、大便潜血等。少见药物不良反应有：腹痛、恶心等。该药的发展历程[3]见图3。 1.作用机制：人体正常生理保护机制[4]如图4：那在正常情况下，抗血栓素（PGI2）与血栓素A2（TxA2）维持着血压和正常的血凝状态。而传统NSAIDs因过度抑制了COX-1而引起消化道损伤，导致能保护胃黏膜的PGI2生成减少；高选择性COX-2抑制剂使COX-2被过分抑制易产生心血管病患，造成体内抗血栓的PGI2生成减少，从而引起抗血栓素的失衡。因此，传统的COX-1与后发展的高选择性的COX-2抑制剂都导致了PGI2与TxA2的失衡。艾瑞昔布，则根据“适度抑制”的理念创制，是在抑制炎症和疼痛的同时，继续去维持体内PGI2与TxA2的平衡，从而降低了胃肠道刺激和心血管损伤的几率。同时，我们将该药与塞来昔布进行COX选择性的比值对比[5]，通过表1更有力说明“适度抑制”到达了适量水平，因而该药是安全有效的、理想的昔布类抗炎药。 2. 构效分析：该药的构效分析见图5。另外，该药中不含有羧基，达到高度选择抑制的优势，即是不会干扰COX-1和COX-2 的氢键结构。与之相反的是，传统的NSAIDs则没有选择性。 3. 代谢作用：该药经过CYP3A酶代谢，其中的4’-甲基氧化为4’-羟甲基化合物1（见图6），其t1/2较短，快速氧化代谢为4’-羧基化合物2，并以2与其葡萄糖醛酸轭合物的形式排出。那通过化学合成得到的化合产物1和2，对COX抑制活性列于表2，我们可以直观地发现这两个代谢产物的选择性和抗炎活性与该药相近[6]。图7则是该药的合成路线图路线，其中原料3是由苯甲硫醚经F-C反应、氧化硫醚成矾，再溴化得到的。图8则是一条更具有生产价值的新路线，将不饱和内酯通过正丙胺胺解，其不饱和内酯直接变换为不饱和内酰胺，在不改变原料的前提下，显著提高了艾瑞昔布的收率和质量。在国内该药研发期间，国外发生了罗非昔布撤市和伐地考昔停用的事件，从而引发了对COX是否是药物靶标的质疑。经过反复学术交流，最终虽然确定了COX酶的药物靶标地位，但对胃肠道和心血管系统的不良反应不可忽视。艾瑞昔布以郭宗儒教授的“适度抑制”理念为设计总纲，经过多次临床试验，其安全性高，耐受性好，不良事件和不良反应发生率低且程度轻，上市后11年里，无一例负面事件，无不在验证其安全、有效。“适度抑制”这一制药理念，始终在影响我们这代制药者。参考文献 [1]李行. 罗非昔布心血管事件始末[J]. 中国处方药, 2004(11):2.[2]https://www.hengrui.com/product/innovativeMedicine.html#pie2.艾瑞昔布片说明书[3]www.docin.com/p-738768477.html?docfrom=rrela[4]郭宗儒.抗炎药物的研制——环氧合酶的适度抑制策略[J].药学学报,2005(11):7-9.DOI:10.16438/j.0513-4870.2005.11.002.[5]郭宗儒.塞来昔布和COX-2选择性抑制剂[J].药学学报,2016,51(06):1010-1016.DOI:10.16438/j.0513-4870.2014-1060.[6]郭宗儒.国家1类新药艾瑞昔布的研制[J].中国新药杂志,2012,21(3):223-230 内容来源于网络，如有侵权，请联系删除。