Construction of Novel Agents having Anti-hypertensive, Nticoaqula- Factors

该项目的特点包括以下几点：(1)通过生物化学家、药学家和有机化学家的密切合作，研究血小板激活因子(PAF)在体内的基础作用，并基于PAF结构构建具有降压、抗凝或抗炎特性的新型药物。(1)通过在甘油骨架C-1位引入不同取代基制得各种衍生物，并进行生物实验(体内外降压和5-羟色胺释放)，证实只有1(S)-Me-PAF具有较强的降大鼠血压和适度激活血小板的作用。因此，它首次被认为是一种选择性激动剂，并使我们设计了一个新的四氢呋喃衍生物，一个构象限制的模型，其活性与PAF相似。(2)利用PAF及其合成类似物研究了不同来源的PAF降解酶的底物专一性。组织源性乙酰水解酶对1(S)-Me-PAF的脱乙酰化略快于1(S)-Me-PAF，而血浆乙酰水解酶对PAF的水解率高于1(S)-Me-PAF。(3)组织源性乙酰水解酶对1(S)-Me-PAF在大鼠肠道的吸收和脱乙酰基作用无明显差异，但PAF的脱乙酰化速度快于1(S)-Me-PAF。(4)对PAF作用的生化研究首次表明，PAF可能通过与PAF特异性结合部位影响一类豚鼠骨髓细胞。以半抗原-牛血清白蛋白结合物免疫兔，制备抗PAF的特异性抗体。

The characteristic features of this project include the following points; (1) the investigation of the basic fole of platelet activating factors (PAF) in the body through close cooperation of biochemists, pharmacologists, and organic chemists and; the construction of novel agents having anti-hypertensive, anticoagulative or anti-inflammative property based on PAF structures. The following results were obtained during the past two years (1986-1988).(1) Various derivative were prepared by introducing various substituents at C-1 position of the glycerin backbone and submitted to the biological test (hypoten- sive effect in vitro and vivo and serotonine release) Lt was confirmed that only 1(S)-Me-PAF strongly reduces the blood pressure of rat and activates moderately platelet. Therefore, it is considered to be a selective agonist for the first time, and brought us to design a novel tetrahydrofuran derivative, a conformationally restricted model, which showed similar activity as PAF.(2) The study of the substrate specificity of PAF-degradating enzymes from various sources was investigated by using PAF and the synthetic analogs. Tissue-originated acetylhydrolases deacetylated 1(S)-Me-PAF slightly faster than PAF, whereas plasma acetylhydrolase hydrolyzed PAF more effectively than 1(S)-Me-PAF.(3) Absorption and deacetylation of 1(S)-Me-PAF at rat intestine were studied and it was shown that there were little differences in the absorption, but PAF was deacetylated more rapidly than 1(S)-Me-PAF.(4) The biochemical study of the role of PAF first suggested that PAF may affect a class of guinea pig bone marurow cells through binding to PAF specific binding sites, resulting in activation and/or induction of differentiation of monocyte- macrophage lineage cells.(5)_ Specific antibodies to PAF were prepared by immunizing rabbits with a hapten-bovine serum albumin conjugate.