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Development of novel photochemical tools to regulate wakefulness

Research Project

Project/Area Number 18K14352
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 37030:Chemical biology-related
Research InstitutionUniversity of Tsukuba

Principal Investigator

Tsuyoshi Saitoh  筑波大学, 国際統合睡眠医科学研究機構, 助教 (80609933)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsオレキシン / 光ケージド薬物 / 睡眠覚醒 / 光反応 / 作動薬 / ケージド化合物 / ケミカルバイオロジー / 神経科学 / 脳・神経 / 有機合成化学
Outline of Final Research Achievements

The development of novel photochemical tools that selectively activate orexin receptors, which physiologically regulate sleep/wakefulness was conducted. As a method for imparting photo-responsiveness to a drug, a photo caging method that can release a drug via covalent bond cleavage by photo-irradiation was adopted. Through the structure-activity relationship study of drug candidates including originally developed OX2R agonists, a candidate drug for caging and its modifiable residue were identified. The inactivated photo-responsive OX2R agonists were synthesized by conjugating a photo-caging group. Photo-irradiation experiments using the synthetic molecules revealed that OX2R agonist was released after the photo-irradiation, and electrophysiological experiments also confirmed the response resulting from OX2R activation after photo-irradiation.

Academic Significance and Societal Importance of the Research Achievements

私たちが睡眠から覚醒に移行する際、どういう分子メカニズムで起きているのか、まだ誰も明らかにしていない。この謎をひもとくためには、覚醒の誘導、維持に重要な役割を果たすオレキシン受容体の機能を時空間解像度高く正確に制御する必要がある。本研究成果は、光という外部刺激によりオレキシン受容体の機能のみを時空間選択的に制御する分子の実現可能性を示すものである。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (10 results)

All 2020 2019 2018

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (7 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results)

  • [Journal Article] Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity.2019

    • Author(s)
      Saitoh T, Seki K, Nakajima R, Yamamoto N, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Tanimura R, Yanagisawa M, Nagase H.
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 29 Issue: 3 Pages: 26552658-26552658

    • DOI

      10.1016/j.bmcl.2019.126893

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity.2019

    • Author(s)
      Saitoh T, Seki K, Nakajima R, Yamamoto N, Kutsumura N, Nagumo Y, Irukayama-Tomobe Y, Ogawa Y, Ishikawa Y, Tanimura R, Yanagisawa M, Nagase H.
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 29 Issue: 18 Pages: 2655-2658

    • DOI

      10.1016/j.bmcl.2019.07.039

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring2019

    • Author(s)
      Yamamoto Naoshi、Ohrui Sayaka、Okada Takahiro、Saitoh Tsuyoshi、Kutsumura Noriki、Nagumo Yasuyuki、Irukayama-Tomobe Yoko、Ogawa Yasuhiro、Ishikawa Yukiko、Watanabe Yurie、Hayakawa Daichi、Gouda Hiroaki、Yanagisawa Masashi、Nagase Hiroshi
    • Journal Title

      Bioorganic & Medicinal Chemistry

      Volume: 27 Issue: 8 Pages: 1747-1758

    • DOI

      10.1016/j.bmc.2019.03.010

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Development of small molecules which regulate the sleep/wake cycle2020

    • Author(s)
      T. Saitoh
    • Organizer
      The 140th Annual Meeting of the Pharmacological Society of Japan
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Essential structure of orexin 1 receptor antagonist YNT-7072019

    • Author(s)
      S. Ohrui, N. Yamamoto, T. Okada, M. Yata, T. Saitoh, N. Kutsumura, Y. Nagumo, Y. Irukayama-Tomobe, Y. Ishikawa, Y. Ogawa, Y. Watanabe, D. Hayakawa, H. Gouda, M. Yanagisawa, H. Nagase
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Discovery of Novel Orexin Receptor Antagonists with 1,3,5-Trioxazatriquinane Skeleton2019

    • Author(s)
      M. Amezawa, J. Horiuchi, T. Saitoh, R. Ohshita, Y. Ogawa, Y. Ishikawa, Y. Irukayama, E. Hasegawa, D. Hayakawa, Y. Watanabe, Y. Nagumo, N. Yamamoto, N. Kutsumura, H. Gouda, T. Sakurai, M. Yanagisawa, H. Nagase
    • Organizer
      The 27th French-Japanese Symposium on Medicinal and Fine Chemistry
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アデノシン2A受容体を標的とした新規光ケージド薬物の創製2019

    • Author(s)
      斉藤毅、井岡秀二、Mustafa Korkutata、千歳洋平、Kaspar Vogt、安倍学、Michael Lazarus、長瀬博
    • Organizer
      第37回メディシナルケミストリーシンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新規低分子量オレキシン2型受容体作動薬、YNT-Xの薬理作用2019

    • Author(s)
      滑川由紀子、入鹿山容子、小川靖裕、石川由紀子、山口拓土、アキンデレ チト、斉藤毅、長瀬博、柳沢正史
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of photocaged adenosine 2A receptor activator2019

    • Author(s)
      Tsuyoshi Saitoh, Shuji Ioka, Mustafa Korkutata, Yohei Chitose, Manabu Abe, Michael Lazarus, Hiroshi Nagase
    • Organizer
      13th International Symposium on Organic Reactions (ISOR-13)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 光ケージドadenosine 2A受容体ポジティブアロステリックモジュレーターの開発2018

    • Author(s)
      井岡秀二、斉藤毅、千歳洋平、Mustafa Korkutata、安部学、Michael Lazarus、長瀬博
    • Organizer
      日本ケミカルバイオロジー学会第13回年会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2021-02-19  

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