Development of novel selective orexin 1 receptor agonists and elucidation of the function of orexin receptors

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03361
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: University of Tsukuba
• Principal Investigator: Nagase Hiroshi 筑波大学, 国際統合睡眠医科学研究機構, 名誉教授 (70383651)
• Co-Investigator(Kenkyū-buntansha): 南雲 康行 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (00459661) ; 斉藤 毅 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80609933)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: オレキシン1受容体 / 作動薬 / オレキシン / 分子設計

Outline of Final Research Achievements

We designed and synthesized a new hybrid molecule focusing on structural similarity based on compounds with an azepine skeleton and a tetralin skeleton that showed weak but detectable OX1R agonist activity. The hybrid molecule showed an OX1R/OX2R dual agonist activity. Since the removal of the biphenyl group dramatically changes the OX2R agonist activity, we then conducted structure-activity relationship studies focusing on the biphenyl moiety and discovered a cinnamate moiety to show OX1R-selective agonist activity. Finally, with the optimization of the substituent on the amide group, we succeeded in the discovery of the first potent OX1R-selective agonist. The in vivo experiments revealed that the OX1R-selective agonist exhibits a remarkable pain-suppressing effect in mice through the activation of OX1R.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

OX1Rは情動や覚醒維持に関与することが知られているが、OX1Rの活性化がどのようなメカニズムでこれら作用を制御しているかは未だ十分に明らかとされておらず、またナルコレプシーなどオレキシン関連疾患におけるOX1R　の役割も不明なままである。従って、OX1Rを選択的に活性化することの出来る作動薬は、これら課題を検討、解決する上で重要なケミカルツールとなる。