Development of novel photochemical tools to regulate wakefulness

• Project/Area Number: 18K14352
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: University 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: ¥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。

Research Products

• [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
  • 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
  • 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 ring (2019)
  • 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
  • Peer Reviewed / Open Access
• [Presentation] Development of small molecules which regulate the sleep/wake cycle (2020)
  • Author(s): T. Saitoh
  • Organizer: The 140th Annual Meeting of the Pharmacological Society of Japan
  • Int'l Joint Research / Invited
• [Presentation] Essential structure of orexin 1 receptor antagonist YNT-707 (2019)
  • 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
  • Int'l Joint Research
• [Presentation] Discovery of Novel Orexin Receptor Antagonists with 1,3,5-Trioxazatriquinane Skeleton (2019)
  • 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
  • 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
• [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
• [Presentation] Development of photocaged adenosine 2A receptor activator (2019)
  • 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)
  • 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