Investigation of the relationship between opioid kappa receptor subtype and receptor dimerization

• Project/Area Number: 23590133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kitasato University
• Principal Investigator: FUJII Hideaki 北里大学, 薬学部, 教授 (30458757)
• Co-Investigator(Renkei-kenkyūsha): NAGASE Hiroshi 筑波大学, 国際統合睡眠医科学研究機構, 教授 (70383651) ; UEZONO Yasuhito 独立行政法人国立がん研究センター, 研究所, 部長 (20213340) ; HIRAYAMA Shigeto 北里大学, 薬学部, 助教 (40565842)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 医薬分子設計 / 受容体ダイマー / オピオイド / κ作動薬 / ファーマコフォー

Research Abstract

On the basis of our 3D pharmacophore model of kappa agonists, compounds belonging to the binding mode 1, 3, or 4 were synthesized and their binding affinities and agonistic activities for the opioid receptors were evaluated. The test compounds showed selective binding abilities and agonistic activities for the kappa receptor although the strengths of bindings and activities depended on the structures. The binding modes of the compounds were not observed to affect the impedance patterns detected by CellKey SystemTM which was used in the functional assays.

Research Products

• [Journal Article] Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure (2014)
  • Author(s): Fujii, H.; Hayashida, K.; Saitoh, A.; Yokoyama, A.; Hirayama, S.; Iwai, T.; Nakata, E.; Nemoto, T.; Sudo, Y.; Uezono, Y.; Yamada, M.; Nagase, H
  • Journal Title: ACS Med. Chem. Lett Volume: 5 Issue: 4 Pages: 368-372
  • DOI: 10.1021/ml400491k
  • Peer Reviewed
• [Journal Article] Essential Structure of theκOpioid Receptor Agonist Nalfurafine for Binding to theκReceptor (2013)
  • Author(s): Nagase, H.; Fujii, H
  • Journal Title: Curr. Pharmacuet. Des Volume: 19 Issue: 42 Pages: 7362-7372
  • DOI: 10.2174/138161281942140105162601
  • Peer Reviewed
• [Journal Article] The effect of 17-N substituents on the activity of the opioid κ receptor in nalfurafine derivatives (2013)
  • Author(s): Nemoto, T.; Hirayama, S.; Iwai, T.; Yamamoto, N.; Harada, Y.; Wada, N.; Tomatsu, M.; Ishihara, M.; Fujii, H.; Nagase, H.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Issue: 1 Pages: 268-272
  • DOI: 10.1016/j.bmcl.2012.10.100
  • Peer Reviewed
• [Journal Article] Essential Structure of the κ Opioid Receptor Agonist Nalfurafine for Binding to the κ Receptor (2013)
  • Author(s): Nagase, H.; Fujii, H.
  • Journal Title: Curr. Pharmacuet. Des. Volume: 19 Issue: 42 Pages: 7400-7414
  • DOI: 10.2174/138161281942140105165011
  • Peer Reviewed
• [Journal Article] Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 3: Synthesis of decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position and their pharmacologies (2012)
  • Author(s): Fujii, H.; Imaide, S.; Hirayama, S.; Nemoto, T.; Gouda, H.; Hirono, S.; Nagase, H.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 24 Pages: 7711-7714
  • DOI: 10.1016/j.bmcl.2012.09.101
  • Peer Reviewed
• [Journal Article] Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 2: Synthesis of decahydro(iminoethano)phenanthrene derivatives and their pharmacologies (2012)
  • Author(s): Nagase, H.; Imaide, S.; Hirayama, S.; Nemoto, T.; Fujii, H.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 15 Pages: 5071-5074
  • DOI: 10.1016/j.bmcl.2012.05.122
  • Peer Reviewed
• [Journal Article] Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies (2012)
  • Author(s): Nagase H、Imaide S、Yamada T、Hirayama S、 Nemoto T、 Yamaotsu N、 Hirono S、 Fujii H
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 60 Issue: 8 Pages: 945-948
  • DOI: 10.1248/cpb.c12-00336
  • NAID: 130001852522
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Presentation] CellKey^<TM>システムを用いた作動活性評価とそれに基づく選択的オピオイドκ受容体作動薬ナルフラフィンの必須構造の検討 (2014)
  • Author(s): 藤井秀明、今出慧海、横山明信、須藤結香、平山重人、岩井孝志、山田貴明、根本徹、上園保仁、長瀬博
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Year and Date: 2014-03-28
• [Presentation] CellKeyTMシステムを用いた作動活性評価とそれに基づく選択的オピオイドκ受容体作動薬ナルフラフィンの必須構造の検討 (2014)
  • Author(s): 藤井秀明、今出慧海、横山明信、須藤結香、平山重人、岩井孝志、山田貴明、根本 徹、上園保仁、長瀬 博
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
• [Presentation] オキサアザトリシクロデカン骨格を有する新規オピオイドδ受容体作動薬の設計と合成、およびその薬理作用2 (2013)
  • Author(s): 藤井秀明、林田康平、渡邉義一、齊藤大祐、高橋俊弘、酒井潤一、田中恵理子、神田貴史、岩井孝志、平山重人、根本徹、山川富雄、長瀬博
  • Organizer: 第33回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2013-09-07
• [Presentation] CellKey™systemを用いた新規δオピオイド受容体特異的アゴニストの開発及びスクリーニング (2013)
  • Author(s): 横山明信、須藤結香、宮野加奈子、鈴木雅美、白石成二、平山重人、林田康平、藤井秀明、酒井潤一、神田貴史、中田恵理子、長瀬博、樋上賀一、上園保仁
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2013-03-22
• [Presentation] オキサアザトリシクロデカン骨格を有する新規オピオイドδ受容体作動薬の設計と合成、およびその薬理作用２ (2013)
  • Author(s): 藤井秀明、林田康平、渡邉義一、齊藤大祐、高橋俊弘、酒井潤一、田中恵理子、神田貴史、岩井孝志、平山重人、根本 徹、山川富雄、長瀬 博
  • Organizer: 第33回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 神戸
• [Presentation] CellKey™ systemを用いた新規δオピオイド受容体特異的アゴニストの開発及びスクリーニング (2013)
  • Author(s): 横山明信、須藤結香、宮野加奈子、鈴木雅美、白石成二、平山重人、林田康平、藤井秀明、酒井潤一、神田貴史、中田恵理子、長瀬博、樋上賀一、上園保仁
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
• [Presentation] オキサアザトリシクロデカン骨格を有する新規オピオイドδ受容体作動薬の設計と合成、およびその薬理作用 (2012)
  • Author(s): 藤井秀明、林田康平、平山重人、岩井孝志、根本徹、酒井潤一、神田貴史、中田理恵子、上園保仁、長瀬博
  • Organizer: 第32回鎮痛薬・オピオイドペプチドシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-09-16