| Project/Area Number |
11557170
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
MATSUNAGA Kimihiro Tohoku University, Graduate School of Pharmaceutical Science, Research Instructor, 大学院・薬学研究科, 助手 (90222306)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Shinya Tohoku University, Graduate School of Pharmaceutical Science, Research Instructor, 大学院・薬学研究科, 助手 (80271849)
NAKAHATA Norimichi Tohoku University, Graduate School of Pharmaceutical Science, Professor, 大学院・薬学研究科, 教授 (60045804)
OHIZUMI Yasushi Tohoku University, Graduate School of Pharmaceutical Science, Professor, 大学院・薬学研究科, 教授 (00006355)
TAKIGUCHI Toshio Lotte Central Laboratory, Co., Ltd., Researcher, 基礎研究所, 研究員
YASUDA Hideyuki Lotte Central Laboratory, Co., Ltd., Researcher, 基礎研究所, 研究員
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 2000: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥8,100,000 (Direct Cost: ¥8,100,000)
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| Keywords | antidepressant / kanokodiol / newrite outgrowth / nerve growth factor / nantenine / 5-HT receptor / structure-activity relationship / molecular modeling / 神経突起伸張作用 / 天然素材 / PC12 |
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| Research Abstract |
Kanokodiol alone did not exhibit the neuritogenic activity, but caused a concentration-dependent enhancement of the nerve growth factor(NGF)-induced neurite outgrowth from PC12D cells. Kanokodiol-induced enhancement of the NGF-action was not affected by GF109203X.PD98059 had no influence on the kanokodiol-induced enhancement of neurite outgrowth in the presence of NGF.No increases in expression of phosphorylated MAPK were observed in kanokodiol-treated PC12D cells in the presence of NGF.These results suggest that kanokodiol enhances the NGF-induced neurite outgrowth from PC12D cells probably by amplifying a down-stream step of MAPK or a parallel pathway to the MAPK cascade in the NGF receptor-mediated intracellular signaling pathway.
Nantenine brought about a marked parallel rightward shift of a concentlation-response curve for 5-HT in the rabbit and rat aorta, rabbit ranal artery or guinea-pig trachea and for norepinephrine in the rabbit and rat aorta, rabbit renal artery and guinea-pig vas deferens. [^3H]Ketanserin binding to the rabbit frontal cortex membrane was inhibited by nantenine. The structure-activity relationship studies on nantenine in the 5-HT_<2A> receptor blocking activity indicated that substitutuion of a methyl group at N-6 and demethylation of a methoxy group at C-1 caused a marked decrease or loss of the activity. Molecular modeling analysis of the interaction between the 5-HT_<2A> receptor and nantenine derivatives suggested that lone pairs of N-6 and of the oxygen atom of methoxy group at C-1 are important to form a hydrogen bond to Asp155 and Asn343 of the 5-HT_<2A> receptor, respectively. These results suggest that nantenine is a competitive antagonist of the 5-HT_<2A> receptor, possessing α_1-adrenergic receptor blocking activity in peripheral tissues. It is also suggested that a methyl group at N-6 and a methoxy moiety at C-1 play important roles in the development of the 5-HT_<2A> receptor blocking activity.
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