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

具有抗高血压、Nticoaqula-因子的新型药剂的构建

• 批准号: 61870094
• 负责人: OHNO Masaji
• 金额: $ 10.88万
• 依托单位: Faculty of Pharmaceutical Sciences, University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research
• 财政年份: 1986
• 资助国家: 日本
• 起止时间: 1986 至 1987
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-61870094/
• 关键词: Platelet Activating Factor; 1(S)-Me-PAF; Phospholipase A_2; Drug Design; Anti- hypertensive; Anti-coagulative; Anti-inflammative; PAF抗体; phospholipase 【A_2】; L-酒石酸

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.

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。

项目成果

Ichiro Kudo, Shoshichi Nojima, Hyeun Wook Chang, Ryohei Yanoshita, Hidetoshi Hayashi, Eri Kondo, Hiroaki Nomura, Keizo Inoue: "Antitumor Activity of Synthetic Alkylphospholipids with or without PAF Activity" Lipids. 22. 862-867 (1987)

Ichiro Kudo、Shoshichi Nojima、Hyeun Wook Chang、Ryohei Yanoshita、Hidetoshi Hayashi、Eri Kondo、Hiroaki Nomura、Keizo Inoue：“具有或不具有 PAF 活性的合成烷基磷脂的抗肿瘤活性”脂质。

Ken Karasawa, Kagari Fujita, Noriko Satoh, Toshio Hongo, Morio Setaka, Masaji Ohno: "Antibody to^1 Platelet Activating Factor (1-0-Alkyl-2-Acetlyl-sn-Glycero- 3-Phosphocholine; paf)" J. Biochem.102. 451-453 (1987)

Ken Karasawa、Kagari Fujita、Noriko Satoh、Toshio Hongo、Morio Setaka、Masaji Ohno：“^1 血小板激活因子抗体（1-0-Alkyl-2-Acetlyl-sn-Glycero- 3-Phosphocholine；paf）” J.

Koki Shigenobu, Yoshio Tanaka, Tomoko Maeda, Yutaka Kasuya: "Potentiation by Bovine Serum Albumin (BSA) of Endo-Thelium-Dependent Vasodilator Response to Acetyl Glyceryl Ether Phosphorylcholine (AGEPC)" J. Pharmacobio-Dyn.10. 220-228 (1987)

Koki Shigenobu、Yoshio Tanaka、Tomoko Maeda、Yutaka Kasuya：“牛血清白蛋白 (BSA) 增强内皮依赖性血管舒张剂对乙酰甘油醚磷酸胆碱 (AGEPC) 的反应”J. Pharmacobio-Dyn.10。

Masaji Ohno, Kagari Fujita, Masafumi Shiraiwa, Akihiro Izumi, Susumu Kobayashi Hirotaka Yoshiwara, Ichiro Kudo, Keizo Inoue, Shoshichi Nojima: "Molecular Design toward Biologically Significant Compounds Based on Platelet Activating Factor: A Highly Select

Masaji Ohno、Kagari Fujita、Masafumi Shiraiwa、Akihiro Izumi、Susumu Kobayashi Hirotaka Yoshiwara、Ichiro Kudo、Keizo Inoue、Shoshichi Nojima：“基于血小板激活因子的具有生物学意义的化合物的分子设计：高度选择

Takayuki Sugiura, Keizo Waku: "Composition of Alkyl Ether-Linked Phospholipids in Mammalian Tissues" Platelet-Activating Factor and Related Lipid Mediators Ed. by Fred Snyder (Plenum Publishing Corporation). 55-85 (1987)

Takayuki Sugiura、Keizo Waku：“哺乳动物组织中烷基醚连接的磷脂的组成”血小板激活因子和相关脂质介质编辑。