Pharmacological study of intarcellular signal transduction using marine natural products as pharmacological tools.

使用海洋天然产物作为药理学工具进行细胞内信号转导的药理学研究。

• 批准号: 12470492
• 负责人: OHIZUMI Yasushi
• 金额: $ 7.1万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470492/
• 关键词: marine natural product; Ca^<2+> channel; Ca^<2+> release; PI-3 kinase; actin; smooth muscle; グラミン誘導体; Ca^<2+>チャンネル; cAMP; ビスプラシン; Ca^<2+>遊離; リアノジン受容体; ユージストニン類

The study of intracellular signal transduction achieved a great advance in these days. However, highly selective pharmacological tools are still required for usage. In our study, we have search the bioactive compounds which target to intracellular signal transduction pathway, isolated from marine organisms and have applied as pharmacological tools. Here, we have succeeded in finding the compounds which affect from input to output of intracellular signal transduction pathway such as on (1) intracellular Ca mobilization, (2) PI-3 kinase, and (3) cytoskelton. Gramine analogues isolated from barnacle showed potent vasorelaxing activity on aortic smooth muscle. This effect was mediated by inhibition of voltage dependent Ca channel. Bisplacin isolated from marine sponge promoted Ca release from sarcoplasmic reticulum with same mechanism as caffeine. We have studied structure-activity relationship of eudistomin D, the known Ca releaser. Halogens in C-5 and C-7 of β-carboline are shown to be necessary for Ca release. Furthermore, methyl moiety in C-9 also representing critical role in Ca releasing activity.We have also studied the role of PI-3 kinase in apoptosis by using halenaquinone isolated from marine sponge as pharmacological tool. We have also showed that goniodomin A which affect on cytoskelton inhibit cell migration.

近年来，细胞内信号转导的研究取得了很大的进展。然而，高度选择性的药物工具仍然需要使用。在我们的研究中，我们从海洋生物中分离出靶向细胞内信号转导途径的生物活性化合物，并将其作为药理工具加以应用。在这里，我们成功地发现了影响细胞内信号转导途径从输入到输出的化合物，如：(1)细胞内Ca动员，(2)PI-3激酶和(3)细胞骨架。从藤壶中分离出的谷氨酰胺类似物对主动脉平滑肌有明显的血管舒张作用。这种效应是通过抑制电压依赖性钙通道介导的。从海绵中分离的双placin促进肌浆网钙的释放，其作用机制与咖啡因相同。我们研究了已知的钙释放剂紫杉醇D的构效关系。β-碳碱C-5和C-7中的卤素被证明是钙释放所必需的。此外，C-9的甲基部分也在钙释放活性中起关键作用。我们还以海绵中分离的卤代醌为药理工具，研究了PI-3激酶在细胞凋亡中的作用。我们还发现影响细胞骨架的性腺蛋白A抑制细胞迁移。

项目成果

Seino-Umeda, A.: "Structure-activity relationships for the Ca^<2+>-releasing activity of 6-hydroxy-β-carboline analogues in skeletal muscle sarcoplasmic reticulum-The effects of halogen substitution at C-5 and C-7"Journal of Pharmacy and Pharmacology. 52.

Seino-Umeda, A.：“骨骼肌肌浆网中 6-羟基-β-咔啉类似物的 Ca^2+-释放活性的结构-活性关系 - C-5 和 C- 上卤素取代的影响7“药学和药理学杂志。52。

Ohi, Y. et al.: "Imaging of Ca^<2+> release by caffeine and 9-methyl-7-bromoeudistomin D and the associated activation of large conductance Ca^<2+>-dependent K^+ channels in urinary bladder smooth muscle cells from the guinea pig"Japanese Journal of Pharm

Ohi, Y. 等人：“咖啡因和 9-甲基-7-bromoeudistomin D 释放 Ca^<2> 的成像以及膀胱平滑肌中大电导 Ca^<2> 依赖性 K^ 通道的相关激活

Abe, M., Inoue, D., Matsunaga, K. Ohizumi, Y. Ueda, H., Asano, T., Murakami, M. & Sato, Y.: "Goniodomin A, an antifungal polyether macrolide, exhibits antiangiogenic activities via inhibition of actin reorganization in endothelial cells."J. Cell. Physiol.

Abe, M.、Inoue, D.、Matsunaga, K. Ohizumi、Y. Ueda, H.、Asano, T.、Murakami, M.

Ohi, Y. et al.: "Imaging of Ca^<2+> release by caffeine and 9-methyl-7-bromosudistomin D and associated activation of large conductance Ca^<2+>-dependent K^+ channels in urinary bladder smooth muscle cells of the guinea"Japanese Journal of Pharmacology. 8

Ohi, Y. 等人：“咖啡因和 9-甲基-7-bromosudistomin D 释放 Ca^2> 的成像以及膀胱平滑肌细胞中大电导 Ca^2 依赖性 K^ 通道的相关激活

Fujiwara, H. et al.: "Halenaquinone, a novel phosphatidylinositol 3-kinase inhibitor from a marine sponge induces apoptosis in PC12 cells"European Journal of Pharmacology. 413. 37-45 (2001)

Fujiwara, H. 等人：“Halenaquinone，一种来自海绵的新型磷脂酰肌醇 3-激酶抑制剂，可诱导 PC12 细胞凋亡”《欧洲药理学杂志》。