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

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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.