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

Research Project

Project/Area Number 20H03361
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionUniversity 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
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2022: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Keywordsオレキシン1受容体 / 作動薬 / オレキシン / 分子設計 / アゴニスト / 創薬化学 / オレキシン受容体 / GPCR / オレキシン1受容体 / 薬理評価 / 機能解明
Outline of Research at the Start

神経ペプチド「オレキシン」を産生するニューロンの後天的欠損は、睡眠覚醒障害であるナルコレプシーの病因である。オレキシン受容体に対する選択的な低分子作動薬の欠如は、疾患に関わるオレキシン受容体の機能解明において大きな足枷となっているだけで無く、ナルコレプシー治療に真に有効な薬物開発を見誤らせる可能性がある。研究代表者らは、世界初のオレキシン1受容体作動薬の創製から薬理学研究までを一貫して実施し、オレキシンがナルコレプシーに及ぼす影響、治療標的としてのオレキシン受容体の有効性を検証する。

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.

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。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (20 results)

All 2023 2022 2021

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (15 results) (of which Int'l Joint Research: 6 results,  Invited: 4 results)

  • [Journal Article] Design and Synthesis of Orexin 1 Receptor-Selective Agonists2023

    • Author(s)
      Keita Iio, Kao Hashimoto, Yasuyuki Nagumo, Mao Amezawa, Taisei Hasegawa, Naoshi Yamamoto, Noriki Kutsumura, Katsuhiko Takeuchi, Yukiko Ishikawa, Hikari Yamamoto, Akihisa Tokuda, Tetsu Sato, Yasuo Uchida, Asuka Inoue, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 66 Issue: 8 Pages: 5453-5464

    • DOI

      10.1021/acs.jmedchem.2c01773

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design and synthesis of novel orexin 2 receptor agonists with a 1,3,5-trioxazatriquinane skeleton2023

    • Author(s)
      Mao Amezawa, Naoshi Yamamoto, Yasuyuki Nagumo, Noriki Kutsumura, Yukiko Ishikawa, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 82 Pages: 129151-129151

    • DOI

      10.1016/j.bmcl.2023.129151

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) librasy2022

    • Author(s)
      Saitoh T, Amezawa M, Horiuchi J, Nagumo Y, Yamamoto N, Kutsumura N, Ohshita R, Tokuda A, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Hasegawa E, Sakurai T, Uchida Y, Sato T, Gouda H, Tanimura R, Yanagisawa M, Nagase H.
    • Journal Title

      Eur J Med Chem

      Volume: 240 Pages: 114505-27

    • DOI

      10.1016/j.ejmech.2022.114505

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring2022

    • Author(s)
      Keita Iio, Tsuyoshi Saitoh, Ryuichiro Ohshita, Tsubasa Hino, Mao Amezawa, Yoshiaki Takayama, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kustumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 60 Pages: 128555-128555

    • DOI

      10.1016/j.bmcl.2022.128555

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design and synthesis of novel orexin 2 receptor agonists based on naphthalene skeleton2022

    • Author(s)
      Tsubasa Hino, Tsuyoshi Saitoh, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 59 Pages: 128530-128530

    • DOI

      10.1016/j.bmcl.2022.128530

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] オレキシン1受容体を介する疼痛制御メカニズムの解析2023

    • Author(s)
      橋本佳応、南雲康行、飯尾啓太、齊藤夕貴、石川有紀子、沓村憲樹、櫻井武、柳沢正史、斉藤毅、長瀬博
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] オレキシン1受容体選択的作動薬の設計と合成2023

    • Author(s)
      長谷川大晟、飯尾啓太、石川有紀子、沓村憲樹、柳沢正史、長瀬博、斉藤毅
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 配座制御に基づく新規テトラリン型OX2R選択的作動薬の創製2023

    • Author(s)
      栗林利明、雨澤真櫻、岡田卓大、大下隆一郎、山本直司、南雲康行、沓村憲樹、入鹿山容子、石川有紀子、柳沢正史、長瀬博、斉藤毅
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Analysis of orexinergic function in chronic pain-like states2023

    • Author(s)
      Kao Hashimoto, Yasuyuki Nagumo, Keita Iio, Yuki Saito, Yukiko Ishikawa, Noriki Kutsumura, Takeshi Sakurai, Masashi Yanagisawa, Tsuyoshi Saitoh, Hiroshi Nagase
    • Organizer
      The 11th Annual WPI-IIIS Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 三次元配向制御に立脚したオレキシン受容体作動薬の創製2023

    • Author(s)
      斉藤毅
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Discovery of orexin receptor agonists2023

    • Author(s)
      Tsuyoshi Saitoh
    • Organizer
      The 15th International Symposium on VIP, PACAP and Related Peptides/The 1st International Society for Bioactive Peptides Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 選択的オレキシン1受容体作動薬の設計と合成2022

    • Author(s)
      飯尾啓太、斉藤毅、橋本佳応、南雲康行、雨澤真櫻、長谷川大晟、石川有紀子、山本直司、沓村憲樹、柳沢正史、長瀬博
    • Organizer
      第39回メディシナルケミストリーシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 1,3,5-Trioxazatriquinane骨格を用いたオレキシン受容体作動薬の創製2022

    • Author(s)
      雨澤真櫻、斉藤毅、山本直司、南雲康行、沓村憲樹、石川有紀子、柳沢正史、長瀬博
    • Organizer
      第39回メディシナルケミストリーシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] TriMER骨格を用いたGPCRリガンド探索ツールの開発2022

    • Author(s)
      雨澤真櫻、斉藤毅、山本直司、南雲康行、沓村憲樹、石川有紀子、柳沢正史、長瀬博
    • Organizer
      第17回GPCR研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 2-メチルテトラリン誘導体を用いたオレキシン受容体作動薬の開発2022

    • Author(s)
      雨澤真櫻、斉藤毅、岡田卓大、大下隆一郎、山本直司、南雲康行、沓村憲樹、入鹿山容子、石川有紀子、柳沢正史、長瀬博
    • Organizer
      第66回日本薬学会関東支部大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Discovery of novel orexin receptor agonists carrying naphthalene skeleton2022

    • Author(s)
      Tsuyoshi Saitoh
    • Organizer
      The 15th International Symposium on Organic Reactions (ISOR-15)
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 意識をハックする分子の創製2022

    • Author(s)
      斉藤毅
    • Organizer
      第9回慶應有機化学若手シンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Discovery of novel orexin receptor antagonists with 1,3,5-trioxazatriquinane skeleton2021

    • Author(s)
      Mao Amezawa; Tsuyoshi Saitoh; Yukiko Ishikawa; Yoko Irukayama; Emi Hasegawa; Hiroaki Gouda; Naoshi Yamamoto; Noriki Kutsumura; Yasuyuki Nagumo; Sakurai Takeshi; Masashi Yanagisawa; Hiroshi Nagase
    • Organizer
      The 2021 International Chemical Congress of Pacific Basin Societies (Pacifichem)(国際学会)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Design and Synthesis of Novel Orexin Receptor Antagonists with 1,3,5-Trioxazatriquinane skeleton2021

    • Author(s)
      Mao Amezawa; Jumpei Horiuchi; Tsuyoshi Saitoh; Ryuichiro Ohshita; Naoshi Yamamoto; Yasuyuki Nagumo; Yukiko Ishikawa; Yoko Irukayama; Emi Hasegawa; Noriki Kutsumura; Ryuji Tanimura; Sakurai Takeshi; Masashi Yanagisawa; Hiroshi Nagase
    • Organizer
      AIMECS2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Design and Synthesis of Novel Orexin Receptor Dual Agonists with Tetralin Skeleton2021

    • Author(s)
      Keita Iio, Tsuyoshi Saitoh, Ryuichiro Ohshita, Tsubasa Hino, Mao Amezawa, Sayaka Ohrui, Takahiro Okada, Yasuyuki Nagumo, Naoshi Yamamoto, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Noriki Kutsumura, Masashi Yanagisawa, Hiroshi Nagase
    • Organizer
      AIMECS2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research

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Published: 2020-04-28   Modified: 2024-12-25  

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