Healing of several PAF-derived diseases by newly disigned PAF antagonists

新设计的 PAF 拮抗剂可治愈多种 PAF 衍生疾病

• 批准号: 02557093
• 负责人: WAKU Keizo
• 金额: $ 9.28万
• 依托单位: Faculty of Pharmaceutical Sciences, Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02557093/
• 关键词: platelet-activating factor; PAF receptor; PAF antagonist; leukocytes; eosinophils; asthma; mast cells; PAF antibody; 血小板活性化因子; アセチルトランスフェラ-ゼ; PAFアンダゴニスト; ラジオイムノアッセイ; ホスホリパ-ゼ; リゾPAF; ノ-アルケニルーGPE

1. Waku, the organizer of this project, studied the production and release of Platelet Activa% Factor(PAF)in the human eosinophils. The A 23187-activated hypodense eosinophils could produce PAF 3-4 times more strongly than the normodence eosinophils and could easily release PAF from the eosinophil cells. The production of superoxide anion(O_2)by the human eosinophils is also studied in comparison with that of human neutrophils. The human eosinophds could produce(O_2)4-5 times more strongly than the human neutrophits on the stimulation by PAF and these results suggest du the damage of lung celts by eosinophils may be due to the strong production of this superoxide anion by the stimulation of PAF.2. Nojima has prepared the PAF antibody by injecting dimethylcarbamoyl-CPGPC to rabbit. This antibody strongly suppressed the platelet coagulation of mbbit and may be useful for protecting animals from the anapbylactic shock caused by PAF.3. Inoue has demo d that the decrease of number of mouse neutrophils by X-ray irradiation was protected by injecdag PAF agonist to the mouse. These results show the role of PAF for the proliferation of neutrophffs in mouse bone marrow.4. Kobayashi has newly designed the PAF antagonist having bicyclo compounds, which is 10 times more effective as an PAF antgonist than the standard PAF antagonist, CV-3988. It is hoped that these newly designed PAF antagonist could be very effective to the PAF receptor of eosinophils.

1. Waku是本项目的组织者，他研究了人嗜酸性粒细胞中血小板活化因子（PAF）的产生和释放。A23187激活的低密度嗜酸性粒细胞产生PAF的能力是正常嗜酸性粒细胞的3-4倍，并能从嗜酸性粒细胞中释放PAF。本文还研究了人嗜酸性粒细胞产生超氧阴离子（O_2）的能力，并与人中性粒细胞作了比较。人嗜酸性粒细胞在PAF刺激下产生的超氧阴离子（O_2）比中性粒细胞强4-5倍，提示嗜酸性粒细胞对肺细胞的损伤可能与PAF刺激下产生的超氧阴离子有关. Nojima用二甲基氨基甲酰基-CPGPC注射家兔制备了PAF抗体。该抗体对血小板的凝血有明显的抑制作用，可能对PAF引起的过敏性休克有一定的保护作用。Inoue等证明，给小鼠注射PAF激动剂可保护X射线照射引起的小鼠中性粒细胞数量的减少。这些结果表明PAF对小鼠骨髓中性粒细胞的增殖有一定的作用.小林新设计了含有双环化合物的PAF拮抗剂，其作为PAF拮抗剂的有效性是标准PAF拮抗剂CV-3988的10倍。这些新设计的PAF拮抗剂有望对嗜酸性粒细胞的PAF受体产生有效的抑制作用。

项目成果

Sugiura,T.,et al.: "Ether-lysophospholipid-induced production of platelet-activating factor in human polymorphonuclear leukocytes" Biochim.Biophys.Acta. 1047. 223-232 (1990)

Sugiura,T.,et al.：“乙醚溶血磷脂诱导人多形核白细胞中血小板活化因子的产生”Biochim.Biophys.Acta。

karasawa,K.,et al.: "Antibodies to synthetic platelet-activating factor analogues with substituents at the sn-2 position" J.Biochem.110. 683-687 (1991)

karasawa,K.,et al.：“在 sn-2 位具有取代基的合成血小板激活因子类似物的抗体”J.Biochem.110。

Kobayashi.S.,et al.: "Development of tetrahydrofuran chiral synthons by enzymatic approach:Improved synthesis of a strong agonist of platelet-activating factor" Tetrahedron Lett.(1992)

Kobayashi.S.等人：“通过酶法开发四氢呋喃手性合成子：改进血小板活化因子强激动剂的合成”Tetrahedron Lett.(1992)

Kudo, I., et al.: "Guinea pig bone marrow cells treated with platelet-activatin factor generate factor (s) which affects their DNA synthesis and microbicidal activity." Lipids. 26. 1065-1070 (1991)

Kudo, I. 等人：“用血小板激活因子处理的豚鼠骨髓细胞会产生影响其 DNA 合成和杀菌活性的因子。”

M.Murakami et al: "Exacerbatation of rat adjuvant arthritis by intradermal injection of purified mammalian 14ーkD_a phos pholipase A_2" FEBS Letter. 268. 113-116 (1990)

M. Murakami 等人：“皮内注射纯化的哺乳动物 14-kD_a 磷酸磷脂酶 A_2 加剧大鼠佐剂关节炎”FEBS Letter 268. 113-116 (1990)。