Elucidation of metabolic rhythm regulation by orexin agonist

• Project/Area Number: 18K11014
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Fukusumi Shoji 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (10750002)
• Co-Investigator(Kenkyū-buntansha): 櫻井 勝康 筑波大学, 国際統合睡眠医科学研究機構, 助教 (70507920) ; 斉藤 毅 筑波大学, 国際統合睡眠医科学研究機構, 助教 (80609933) ; 入鹿山 容子 筑波大学, 国際統合睡眠医科学研究機構, 研究員 (90312834)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 睡眠 / オレキシン / オレキシン受容体作動薬

Outline of Final Research Achievements

We demonstrate the potential metabolic effects of a non-peptide OX2R selective agonist, YNT-185 by using high-fat fed mice. C57BL/6J mice was single-housed under high-fat diet for one week and daily intraperitoneal administration of YNT-185 or vehicle was performed during light period (ZT6). As a result, the body weight gain of the YNT-185-treated group was attenuated along with the decrease in the food intake compared to the control group. Moreover, the weights of epididymal adipose tissues in the YNT-185-treated group were significantly reduced compared to the control group. It is suggested that the YNT-185 attenuates diet-induced body weight gain by reducing the accumulation of peripheral fat at least via suppression of food intake. The pharmacological effects may depend on the clock time of the administration. To validate the effectiveness on metabolic abnormalities, the pharmacological mechanisms of YNT-185 against body weight gain need to be elucidated by further investigation.

Academic Significance and Societal Importance of the Research Achievements

メタボリックシンドローム、いわゆる肥満は多くの場合、合併症により健康寿命を短くし、QOLの低下を招くだけでなく、医療費を圧迫するなど大きな社会問題となっている。一方、代謝改善薬としてオレキシン系を標的にしたものは現在のところ存在しない。今回の結果から、オレキシン2型受容体作動薬は将来的に全く新しい機序の代謝改善薬として有望である。また、既存の治療法とは作用部位が異なるため、既知の治療法との併用により相加・相乗効果が期待できる。

Research Products

• [Journal Article] Design and synthesis of novel orexin antagonists via structural simplification of the morphinan skeleton. (2021)
  • Author(s): Ohrui S, Irukayama-Tomobe Y, Ishikawa Y, Yanagisawa M, and Nagase H.
  • Journal Title: Heterocycles Volume: - Issue: 2 Pages: 929-929
  • DOI: 10.3987/com-20-s(k)63
  • Peer Reviewed / Open Access
• [Journal Article] Effects of body pillow use on sleeping posture and sleep architecture in healthy young adults (2021)
  • Author(s): Park, I., Suzuki, C., Suzuki, Y., Kawana, K., Yajima, K., Fukusumi, S., Kokubo, T., Tokuyama, K., Yanagisawa, M., Satoh, M
  • Journal Title: Sleep Medicine Research Volume: Accepted
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine (2020)
  • Author(s): Nagumo Yasuyuki、Katoh Koki、Iio Keita、Saitoh Tsuyoshi、Kutsumura Noriki、Yamamoto Naoshi、Ishikawa Yukiko、Irukayama-Tomobe Yoko、Ogawa Yasuhiro、Baba Takeshi、Tanimura Ryuji、Yanagisawa Masashi、Nagase Hiroshi
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 30 Issue: 17 Pages: 127360-127360
  • DOI: 10.1016/j.bmcl.2020.127360
  • Peer Reviewed / Open Access
• [Journal Article] Subacute ingestion of caffeine and oolong tea increases fat oxidation without affecting energy expenditure and sleep architecture: a randomized, placebo-controlled, double-blinded cross-over trial. (2020)
  • Author(s): Zhang, S., Takano, J., Murayama, N., Tominaga, M., Abe, T., Park, I., Seol, J., Ishihara, A., Tanaka, Y., Yajima, K., Suzuki, Y., Suzuki, C., Fukusumi, S., Yanagisawa, M., Kokubo, T., Tokuyama, K.
  • Journal Title: Nutrients. Volume: 12 Issue: 12 Pages: 3671-1680
  • DOI: 10.3390/nu12123671
  • Peer Reviewed
• [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 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] OX2R-selective orexin agonism is sufficient to ameliorate narcoleptic symptoms, cataplexy and sleep/wakefulness fragmentation in mouse models. (2020)
  • Author(s): Yamamoto H, Irukayama-Tomobe Y, Ishikawa Y, Namekawa Y, Nemoto T, Tanaka H, Takahashi G, Yanagisawa M.
  • Organizer: 第93回日本薬理学会年会
• [Presentation] In vitro and in vivo pharmacology of small-molecule orexin agonists for treatment of narcolepsy (2019)
  • Author(s): 1.Namekawa Y, Irukayama-Tomobe Y, Ishikawa Y, Yamaguchi T, Ogawa Y, Nemoto T, Tanaka H, Yamamoto H, Tito Akindele, Saitoh T, Nagase H, Yanagisawa M
  • Organizer: Tsukuba Global Science Week
  • Int'l Joint Research
• [Presentation] Essential structure of orexin 1 receptor antagonist YNT-707 (2019)
  • Author(s): 2.Ohrui S, Yamamoto N, Okada T, Yata M, Saitoh T, Kutsumura N, Nagumo N, Irukayama-Tomobe Y, Ishikawa Y, Ogawa Y, Watanabe Y, Hayakawa D, Gouda H, Yanagisawa M, Nagase H.
  • Organizer: 27th International Society of HeterocyclicChemistry Congress ROHM Theatre Kyoto & Miyakomesse
  • Int'l Joint Research
• [Presentation] Discovery of Novel Orexin Receptor Antagonist with 1,3,5-Trioxazatriquinane Skeleton (2019)
  • Author(s): 3.Amezawa M, Horiuchi J, Saitoh T, Ogawa Y, Ishikawa Y, Irukayama Y, Hasegawa E, Hayakawa D, Watanabe Y, Nagumo Y, Yamamoto N, Kutsumura N, Gouda H, Sakurai T, Yanagisawa M, Nagase H.
  • Organizer: The 27th French-Japanese Symposium on Medicinal and Fine Chemistry Hotel Leopalace Hakata
• [Presentation] Non-peptidic Orexin receptor type-2 agonist attenuates body weight gain of high-fat fed mice (2018)
  • Author(s): 1.Eriya Takahashi*, Kyoko Enomoto, Takuto Yamaguchi, Yasuhiro Ogawa, Shoji Fukusumi, Akari Kawai, Masaya Araki, Tsuyoshi Saitoh, Yoshimi Nakagawa, Yoko Irukayama-Tomobe, Hitoshi Shimano, Hiroshi Nagase, Masashi Yanagisawa
  • Organizer: The 41st Annual Meeting of the Japan Neuroscience Society
  • Int'l Joint Research