2019 Fiscal Year Final Research Report
Development of polycyclic heterocyclic compounds as GPCR analogues
| Project/Area Number |
17K08369
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Yokohama College of Pharmacy (2019)
Health Sciences University of Hokkaido (2017-2018) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
町支 臣成 福山大学, 薬学部, 教授 (10248297)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 多環縮環型複素環 / フラン環 / ペリ環状反応 / Gタンパク質共役型受容体 / アゴニスト / 抗腫瘍活性物質 / 生物活性物質 |
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| Outline of Final Research Achievements |
G protein coupled receptors (GPCRs) are identified the 7th transmembrane receptor, and take essential roles in many pshysiological homeostasis. Serotonin 2C receptor (5-HT2C receptor) classifies as seventh transmembrane domain receptors coupled to G proteins (GPCRs). It was expressed on the central nervous system; relatively higher expressed at amygdala, hippocampus, and hypothalamus. As the receptor was related to the emotion and food intake according to the analysis on 5-HT2C receptor KO mice, and the lorcaserin was discovered against anti-obesity drug. In current study, we synthesized benzofuro[3,2-c]pyridine analogues by using MW-assisted thermal electrocyclic reaction, and assessed their efficacy against 5-HT2C activation. Furthermore, some polycyclic heterocycles were indicated potent antiproliferative activity in tumor cells.
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| Free Research Field |
創薬化学
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| Academic Significance and Societal Importance of the Research Achievements |
Gタンパク質共役型受容体のX線結晶構造解析の発展に伴って、そのアンタゴニストの開発では、SBDD（Structure based drug design）が適応され始めてきている。一方、GPCRアゴニストの開発では、アゴニストと受容体の複合体解析の結果が乏しく、未だ化合物ライブラリーに依存した創薬が主流である。本研究では、構造的に強固な5HT2Cアゴニストを創生したことで、アゴニストの立体構造を基に、ファーマコフォアの構築を模索することが可能と考えられる。
また、多環縮環型複素環ライブラリーより、新規抗腫瘍活性物質の創生に成功しており、保健医療の分野においても多大な貢献が確信される。
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