The adsorption of endothelin 1 to phospholipids is governed by electrostatic interactions: A monolayer and fluorescence study

In order to elucidate the influence on the lipidic environment on the recognition process of its membrane associated receptor, the interactions of the vasoconstrictor peptide endothelin 1 with various phospholipids have been investigated using different lipidic model membranes: monolayers at constant surface pressure, vesicles and micelles. A monolayer study of ET1 adsorbed onto the water surface has shown that the C-terminus of the peptide points towards the aqueous phase. Penetration measurements into lipidic monolayers indicate that ET1 adsorbs to phospholipids with an orientation similar to that of the air–water interface and fluorescence measurements are in agreement with such an orientation of the peptide. This adsorption is selective for neutral phospholipids and indicates that the nature of the phospholipid headgroups is of major importance for the approach of the membrane associated receptor.     

SELECTIVE ALKYLATION/ACYLATION OF DI- OR TRIANIONS: EXPEDITIOUS DERIVATIZATION OF ENDOTHELIN ANTAGONISTS[1]

ABSTRACT

Sitaxsentan sodium (1, TBC11251Na) is an ET_A selective endothelin antagonist under clinical development for pulmonary arterial hypertension and congestive heart failure. Second generation compounds, as exemplified by TBC2576 (2) are currently under development in our laboratories. To rapidly access analogs of 1 and 2, a route was developed for the selective alkylation or acylation of the corresponding di- or trianions derived from these two highly functionalized compounds. We report here on this straightforward, yet effective, procedure consisting of treating the di- or trianions with an excess amount of electrophiles, followed by a rapid quench. In this manner, selective alkylation or acylation of 1 and 2 was achieved with satisfactory yields.     

NO样舒张因子和内皮素在急性缺氧肺动脉高压中的作用

在大鼠急性缺氧肺动脉高压模型、离体灌流肺动脉环模型及培养的牛肺动脉内皮细胞探讨ＮＯ样舒张因子（ＮＯ－ＬＲＦ）和内皮素（ＥＴ）在急性缺氧肺动脉高压中的作用。结果发现：ＮＯ合成前体Ｌ－Ａｒｇ（２５０ｍｇ／ｋｇ，ｉｖ）可有效降低急性缺氧肺动脉高压的幅度；在内皮完整血管环加入ＮＯ合成抑制剂Ｌ－ＮＮＡ（１０－４ｍｏｌ／Ｌ）、ＮＯ合成前体Ｌ－Ａｒｇ（１０－２ｍｏｌ／Ｌ）分别升高（＋８０％，Ｐ＜０．０１）和降低（－３５％，Ｐ＜０．０５）缺氧肺动脉收缩幅度，给予硝酸甘油（１０－４ｍｏｌ／Ｌ）直接补充ＮＯ可降低缺氧肺动脉收缩幅度；此效应可被可溶性鸟苷酸环化酶抑制剂亚甲蓝部分逆转；内皮素抗血清或内皮素Ａ受体结抗剂ＢＱ１２３对急性缺氧肺动脉高压及缺氧肺动脉收缩没有明显影响；Ｎｏｒｔｈｅｒｎ印渍杂交技术显示缺氧使培养的牛肺动脉内皮细胞ＮＯ合成酶（ＮＯＳ）基因表达明显受抑乃至缺失．结果提示：缺氧时ＮＯＳ基因表达受抑及ＮＯ－ＬＲＦ合成释放降低可能是急性缺氧肺动脉高压的发生机制之一，内皮素不起主要作用．     

γ-羟基丁烯羟酸内酯类内皮激素拮抗剂的比较分子场分析

采用比较分子场分析方法（CoMFA)分析了一组γ-羟基丁烯羟酸内酯类内皮激素拮抗剂的活性与结构的关系。在计算中,除了考察立体场和静电场,还引入了氢键场,结果表明,引入氢键场可以明显改善计算的结果。所得模型不仅能够很好地预测训练集中的分子,而且还可准确地预测测试集中的化合物。通过分析分子场等值面图在空间的分布,可以观察到叠合分子周围的立体、静电以及氢键特征对化合物活性的影响。     

Total synthesis of endothelin 1 by microwave-assisted solid phase method

<正>A microwave-assisted solid phase synthesis for endothelin 1 is presented.Reduced endothelin 1 was synthesized efficiently on Wang resin under microwave irradiation using Fmoc/tBu orthogonal protection strategy.The whole peptide was cleaved from the resin and two disulphide bridges were formed under air oxidation at room temperature.The purity and efficiency of synthesizing the peptide is much higher than other methods used before.     

内皮素与心血管疾病

内皮素是一种血管活性多肽，是目前已知的最强的缩血管物质，它除参与心血管系统的机能调节外，还与多种心血管疾病有关。     

内皮素与妇产科疾病

为探讨内皮素含量的高低与某些妇产科疾病的关系，从内皮素的产生、分布及其与妇产科疾病的关系等方面进行了简要综述。     

The Barton reaction using a microreactor and black light. Continuous-flow synthesis of a key steroid intermediate for an endothelin receptor antagonist

The Barton reaction (nitrite photolysis) of a steroidal substrate 1, to give 2, a key intermediate for the synthesis of an endothelin receptor antagonist, was successfully carried out in a continuous microflow system using a pyrex glass-covered stainless-steel microreactor having a microchannel (Type A: 1000 μm width, 107 μm depth, 2.2 m length). We found that a 15 W black light (peak wavelength: 352 nm) as the light source, suffices for the Barton reaction, creating a compact photo-micro reaction system. Multi-gram scale production was attained using two serially connected, multi-lane microreactors (Type B).     

内皮素对心脏功能的影响

内皮素(Endothelin,ET)是由血管内皮细胞产生的具有强烈缩血管作用的血管活性肽.大量实验表明,内皮素对心脏具有广泛的影响,使冠状血管收缩,对心脏产生正性肌力作用,通过内皮素受体参与神经体液因素对心肌细胞的调节作用.     

实验性酒精性肝病血浆内皮素浓度的变化

为探讨内皮素（ＥＴ）在酒精性肝病中的作用，本实验采用每日分次灌胃的方法建立了酒精性肝病的大鼠模型，采用放射免疫技术动态测定酒精性肝病大鼠和正常大鼠血浆中内皮素浓度的变化。结果：酒精喂饲的大鼠其血浆内皮素浓度明显高于相应的正常对照组，而且随着酒精性肝病病变程度的加重，内皮素浓度也相应升高。结论：内皮素水平的升高可能与酒精性肝损伤有关，因为内皮素有强大的缩血管作用，可使肝血流减少，而这是酒精性肝病的发病的发病机制之一。