Development of novel molecular tool for controlling sleep/wake cycle and feeding behavior

• Project/Area Number: 15K16557
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: University of Tsukuba
• Principal Investigator: SAITOH Tsuyoshi 筑波大学, 国際統合睡眠医科学研究機構, 助教 (80609933)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: オレキシン / 睡眠覚醒 / 光ケージド化合物 / 作動薬 / 睡眠 / 覚醒 / ケージド化合物 / 拮抗薬 / スイッチング化合物 / 合成化学 / 神経科学 / 脳・神経 / 有機化学

Outline of Final Research Achievements

Purpose of this project is to develop novel molecular tool for controlling sleep/wake cycle and feeding behavior. Especially, we employed photo-caging technique to control the orexin agonist activity with light. Our main discoveries are the followings; 1) We discovered novel potent and selective orexin 2 receptor agonist YNT-185 and explored the target brain region of this molecule. 2) We designed and synthesized photo-caged orexin receptor agonist based on the structure-activity relationship study of orexin receptor agonist. 3) The caged molecule was investigated the photoresponcibility and electrophisiological responce.

Research Products

• [Journal Article] Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity (2018)
  • Author(s): Ohrui Sayaka、Yamamoto Naoshi、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: Bioorg Med Chem Lett. Volume: 28 Issue: 4 Pages: 774-777
  • DOI: 10.1016/j.bmcl.2017.12.069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats (2018)
  • Author(s): Toyama, S., Shimoyama N, Tagaito Y., Nagase H., Saitoh T., Yanagisawa M., and Shimoyama, M.
  • Journal Title: Anesthesiology Volume: 128 Issue: 5 Pages: 992
  • DOI: 10.1097/aln.0000000000002161
  • Peer Reviewed
• [Journal Article] オレキシン研究の進展と新規受容体作動薬の創製 (2018)
  • Author(s): 斉藤毅，長瀬博
  • Journal Title: バイオサイエンスとインダストリー(B&I) Volume: 76 Pages: 127-29
• [Journal Article] Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models (2017)
  • Author(s): Irukayama-Tomobe Y, Ogawa Y, Tominaga H, Ishikawa Y, Hosokawa N, Ambai S, Kawabe Y, Uchida S, Nakajima R, Saitoh T, Kanda T, Vogt K, Sakurai T, Nagase H, Yanagisawa M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 22 Pages: 5731-5736
  • DOI: 10.1073/pnas.1700499114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor (2017)
  • Author(s): Yamamoto Naoshi、Ohrui Sayaka、Okada Takahiro、Yata Masahiro、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: Bioorg Med Chem Lett. Volume: 27 Issue: 17 Pages: 4176-4179
  • DOI: 10.1016/j.bmcl.2017.07.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IIIS発 ナルコレプシー治療薬開発に向けた取り組み (2017)
  • Author(s): 斉藤毅，入鹿山容子，柳沢正史，長瀬博
  • Journal Title: なるこ Volume: 34 Pages: 8-10
• [Journal Article] Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies (2017)
  • Author(s): Nagase H and Yanagisawa M et al.
  • Journal Title: J Med Chem Volume: 60 Issue: 3 Pages: 1018-1040
  • DOI: 10.1021/acs.jmedchem.6b01418
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 睡眠覚醒を制御する世界初の分子：オレキシン２受容体作動薬YNT-185の創製 (2016)
  • Author(s): 斉藤 毅，長瀬 博
  • Journal Title: 和光純薬時報 Volume: 84 Pages: 2-5
• [Journal Article] 低分子オレキシン受容体アゴニストの創製 (2016)
  • Author(s): 斉藤 毅，長瀬 博
  • Journal Title: MEDCHEM NEWS Volume: 26 Pages: 90-96
  • NAID: 130007383316
  • Peer Reviewed
• [Journal Article] Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists (2015)
  • Author(s): Nagahara T, Saitoh T, Kutsumura N, Irukayama-Tomobe Y, Ogawa Y, Kuroda D, Gouda H, Kumagai H, Fujii H, Yanagisawa M, Nagase H
  • Journal Title: J. Med. Chem Volume: 58 Issue: 20 Pages: 7931-7937
  • DOI: 10.1021/acs.jmedchem.5b00988
  • Peer Reviewed
• [Presentation] 低分子量オレキシン受容体2型作動薬YNT-185の組織学的、及び電気生理学的解析 (2017)
  • Author(s): 小川靖裕、入鹿山容子、富永拡、細川直人、斉藤毅、長瀬博、柳沢正史
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎新聞文化ホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] 新規低分子量オレキシン受容体作動薬YNT-185の全身炎症後の活動回復作用の検討 (2017)
  • Author(s): 内田俊太郎、入鹿山容子、小川靖裕、富永拡、石川ゆい、木山麻衣子、斉藤毅、長瀬博、柳沢正史
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎新聞文化ホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] モルヒナン骨格を有するオレキシン1受容体（OX1R）の特異的拮抗薬の設計・合成とOX1R結合の活性立体配座 (2017)
  • Author(s): 山本直司、大類彩、岡田卓大、谷田誠浩、斉藤毅、沓村憲樹、南雲康行、入鹿山容子、小川靖裕、石川有紀子、平山重人、渡辺友里恵、早川大地、合田浩明、柳沢正史、長瀬博
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] Design and synthesis of orexin 1 receptor selective antagonists (2017)
  • Author(s): Sayaka Ohrui, Naoshi Yamamoto, Masahiro Yata, Takahiro Okada, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Yasuhiro Ogawa, Shigeto Hirayama, Masashi Yanagisawa, Hiroshi Nagase
  • Organizer: Tsukuba Global Science Week (TGSW) 2017
  • Int'l Joint Research
• [Presentation] オレキシン１受容体拮抗薬YNT-707の必須構造部位検討 (2017)
  • Author(s): 大類彩、山本直司、岡田卓大、谷田誠浩、斉藤毅、沓村憲樹、南雲康行、入鹿山容子、石川有紀子、小川靖裕、渡邊友里恵、早川大地、合田浩明、柳沢正史、長瀬博
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] 大学における創薬研究とクロマトグラフィー (2017)
  • Author(s): 斉藤毅
  • Organizer: 分取クロマトセミナー2017
  • Invited
• [Presentation] 睡眠覚醒を標的とする創薬研究 (2017)
  • Author(s): 斉藤毅
  • Organizer: 第４回次世代の有機化学・広島シンポジウム
  • Invited
• [Presentation] オレキシン 2 受容体作動薬 YNT-185 の創製 (2016)
  • Author(s): 斉藤毅、永原崇志、沓村憲樹、中嶋龍、細川直人、入鹿山容子、小川靖裕、富永拡、黒田大介、合田浩明、藤井秀明、柳沢正史、長瀬博
  • Organizer: 第34回メディシナルケミストリーシンポジウム サテライトセッション
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] 低分子オレキシン受容体アゴニストの創製 (2016)
  • Author(s): 斉藤毅、永原崇志、沓村憲樹、入鹿山容子、小川靖裕、富永拡、黒田大介、合田浩明、藤井秀明、柳沢正史、長瀬博
  • Organizer: 第60回日本薬学会関東支部大会
  • Place of Presentation: 東京大学本郷キャンパス（東京都文京区）
  • Year and Date: 2016-09-17
  • Invited
• [Presentation] オレキシン2受容体作動薬の設計・合成 (2016)
  • Author(s): 長瀬博、永原崇志、斉藤毅、沓村憲樹、入鹿山容子、小川靖裕、黒田大祐、合田浩明、藤井秀明、柳沢正史
  • Organizer: 第36回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 北海道大学（北海道札幌市）
  • Year and Date: 2016-08-19
  • Invited
• [Presentation] Development of non-peptide orexin receptor agonists for controlling sleep/wake cycle (2016)
  • Author(s): Tsuyoshi Saitoh, Takashi Nagahara, Noriki Kutsumura, Yoko Irukayama, Yasuhiro Ogawa, Daisuke Kuroda, Hiroaki Gouda, Hideaki Fujii, Masashi Yanagisawa, Hiroshi Nagase
  • Organizer: 日本化学会第96春季年会
  • Place of Presentation: 同志社大学京田辺キャンパス、京都府、京都市
  • Year and Date: 2016-03-27
• [Presentation] Discovery of novel orexin receptor agonists for controlling sleep/awake cycle (2015)
  • Author(s): T. Saitoh, T. Nagahara, N. Kutsumura, Y. Irukayama, Y. Ogawa, H. Fujii, M. Yanagisawa, H. Nagase
  • Organizer: Pacifichem 2015
  • Place of Presentation: ヒルトンハワイアンビレッジ、ホノルル、アメリカ
  • Year and Date: 2015-12-19
  • Int'l Joint Research
• [Presentation] 低分子オレキシン受容体アゴニストの創製 (2015)
  • Author(s): 斉藤毅、永原崇志、沓村憲樹、入鹿山容子、小川靖裕、黒田大祐、合田浩明、藤井秀明、柳沢正史、長瀬博
  • Organizer: 第33回 メディシナルケミストリーシンポジウム
  • Place of Presentation: 幕張国際研修センター、千葉県、千葉市
  • Year and Date: 2015-11-26