Development of novel orexin ligand and its pharmacological activity
| Project/Area Number |
16H05098
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Nagase Hiroshi 筑波大学, 国際統合睡眠医科学研究機構, 特命教授 (70383651)
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| Co-Investigator(Kenkyū-buntansha) |
桜井 武 筑波大学, 医学医療系, 教授 (60251055)
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)
柳沢 正史 筑波大学, 国際統合睡眠医科学研究機構, 教授 (20202369)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2016: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
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| Keywords | オレキシン / オピオイド / モルヒナン / 作動薬 / 拮抗薬 / OX1R作動薬 / モルフィナン骨格 / OX1R拮抗薬 / OX2R作動薬 / 創薬化学 / 有機合成化学 / ナルフラフィン / オレキシン受容体 / 睡眠 / 覚醒 / ナルコレプシー |
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| Outline of Final Research Achievements |
This study aimed at the development of novel orexin receptor agonists, especially OX1R selective agonists, to understand the function of the orexinergic system in the regulations of sleep/wake cycles and food intake.
Since agonists and antagonists often have similar structures, we planned to design OX1R agonists from the structure of OX1R antagonist YNT-707, which has our uniquely developed morphinan skeleton.
The structure-activity relationship studies of YNT-707 clarified the structural units responsible for the antagonist activity of YNT-707 as well as receptor affinity, and we found that the unique conformation of two pharmacophores is essential for the high OX1R selectivity.
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| Academic Significance and Societal Importance of the Research Achievements |
オレキシンは睡眠と覚醒のサイクルや摂食行動の制御に関与する生体内神経ペプチドであり、OX1RとOX2Rに作用する。特に、覚醒の制御に関してはOX2Rの機能が重要であると報告されており、OX2R選択的作動薬は睡眠疾患ナルコレプシーの治療薬として期待されている。一方、OX1Rに関しては薬物依存や疼痛緩和等に関与すると考えられているが、これらはオレキシンペプチドを用いた研究報告によるものであり、受容体自体の機能や薬理作用についてはほとんど何も分かっていない。OX1Rの真の機能解明のためにも、OX1R選択的な作動薬や拮抗薬の開発研究は意義のあるものである。
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Report
(4 results)
Research Products
(42 results)
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[Journal Article] Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models2017
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.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 114
Issue: 22
Pages: 5731-5736
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Design and synthesis of orexin 1 receptor selective antagonists2017
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
Related Report
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[Presentation] Synthesis of Novel, Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton2016
Author(s)
Naoshi Yamamoto, Masahiro Yata, Sayaka Ohrui, Takahiro Okada, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Yasuhiro Ogawa, Daisuke Kuroda, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase
Organizer
The 25th French-Japanese Symposium on Medicinal and Fine Chemistry
Place of Presentation
Keio Plaza Hotel Tama（東京都多摩市）
Year and Date
2016-05-16
Related Report
Int'l Joint Research
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