CHARACTERIZATION OF HEART ATRIAL MUSCARINIC RECEPTOR

心房毒蕈碱受体的表征

• 批准号: 3337345
• 负责人: Michael Schimerlik
• 金额: $ 15.99万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-12-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3337345
• 关键词: acetylcholine; affinity chromatography; angiosperms; antibody; anticholinergic agent; antineoplastics; atrium; binding proteins; chemical reaction; cholinergic agents; density gradient ultracentrifugation; fluorescent dye /probe; gel filtration chromatography; guanine nucleotides; guanylate cyclase; heart pharmacology; ligands; membrane proteins; muscarinic receptor; protein structure function; radiotracer; swine; thermodynamics

A new procedure for the rapid isolation of additional homologues of the cytotoxic linear bistetrahydrofuranoid acetogenins rollinicin and rollinone from Rollinia papilionella, R. sericea, and R. microsepala will be investigated. Several of these acetogenins have shown in vivo activity against the P388 lymphocytic leukemia in mice. Additional homologues will be isolated with the use of a Sephadex column and will be characterized using NMR and mass spectral methods. Since the mechanism of action of these antineoplastic compounds is not known, a structure-activity study will be initiated to determine which functional groups are required to demonstrate cytotoxic activity. The acetogenins, particularly the bistetrahydrofuran moiety, are sensitive to a variety of reaction conditions. Therefore, model compounds will be synthesized and used to develop the reaction conditions to be used to modify the active principles. The bistetrahydrofuran portion of the model compounds will be synthesized via a 'zipper' reaction of an appropriate triepoxide. The triepoxide will be prepared from the corresponding triene which will be constructed via a series of Wittig reactions. The decomposition products of clinical samples of maytansine will be isolated and identified by NMR and mass spectral methods. the identification of these decomposition products may provide some insight into the metabolism of maytansine when administered as an antineoplastic drug. Minor maytansinoids will be isolated from Maytenus rothiana, M. senegalensis, and M. putterlickoides. These maytansinoids will be identified by comparisons to known maytansinoids and by NMR and mass spectral data. New maytansinoids will be screened for cytotoxicity and may be prepared in larger quantities by semi-synthesis from maytansinol for in vivo testing. Modified maytansinoids will also be prepared from maytansinol for further evaluation of the structure-activity relationships in this series of potent antineoplastic agents. Modifications of the side chain ester and ether derivatives will be prepared. Activity-guided fractionation of extracts of Schrebera alata and Gypsophilia paniculata will also be initiated.

一种快速分离其他同源物的新方法 细胞毒性线性双四氢呋喃类乙酰基罗林辛和罗林农 来自 Rollinia papilionella、R. sericea 和 R. microsepala 将是 调查了。 其中一些 acetogenins 已显示出体内活性 对抗小鼠 P388 淋巴细胞白血病。 额外的同系物将 使用 Sephadex 柱进行分离并进行表征 使用核磁共振和质谱方法。 由于作用机制 这些抗肿瘤化合物尚不清楚，结构活性研究 将启动以确定需要哪些职能组 表现出细胞毒活性。 乙酰胆碱，特别是 双四氢呋喃部分，对多种反应敏感 状况。 因此，模型化合物将被合成并用于 开发用于修饰活性物质的反应条件 原则。 模型化合物的双四氢呋喃部分将是 通过适当的三环氧化物的“拉链”反应合成。 这 三环氧化物可由相应的三烯制备， 通过一系列维蒂希反应构建。 美登素临床样品的分解产物将是 通过核磁共振和质谱方法分离和鉴定。 这 识别这些分解产物可能会提供一些见解 当作为抗肿瘤药物给药时，会影响美登素的代谢 药品。 次要的美登木素生物碱将从 Maytenus rothiana, M. 中分离出来。 senegalensis 和 M. putterlickoides。 这些美登木素生物碱将是 通过与已知的美登木素生物碱比较以及通过 NMR 和质量鉴定 光谱数据。 将筛选新的美登木素生物碱的细胞毒性，并可能 通过半合成美登醇可大量制备 体内测试。 修饰的美登木素生物碱也将由 美登醇用于进一步评估结构-活性关系 在这一系列强效抗肿瘤药物中。 侧面的修改 将制备链酯和醚衍生物。 Schrebera alata 提取物的活性引导分馏 满天星也将启动。