Clarification of the optimal orientation and length of the side chain in opioid kappa receptor ligands and its application

• Project/Area Number: 26860076
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: University of Tsukuba
• Principal Investigator: YAMAMOTO Naoshi 筑波大学, 国際統合睡眠医科学研究機構, 助教 (80580216)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: κ受容体作動薬 / オピオイド / モルヒナン

Outline of Final Research Achievements

The synthetic route for the 4,5-epoxymorphinan derivatives with a bicycle[2.2.2]octane skeleton from naltrexone hydrochloride was established. The F-ring contained 4,5-epoxymorphinan derivatives with the side chain characterized by an orientation and a length were prepared and assayed for the affinity for opioid receptors. As a result, the derivative with a benzyl amide side chain oriented in the same plane of the F-ring showed potent activity and high selectivity for opioid kappa receptor.

Research Products

• [Journal Article] Synthesis of new opioid derivatives with a propellane skeleton and their pharmacologies: Part 5, novel pentacyclic propellane derivatives with a 6-amide side chain (2015)
  • Author(s): Nakajima R, Yamamoto N, Hirayama S, Iwai T, Saitoh A, Nagumo Y, Fujii H, Nagase H.
  • Journal Title: Bioorg Med Chem. Volume: 23 Issue: 19 Pages: 6271-6279
  • DOI: 10.1016/j.bmc.2015.08.036
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ナルフラフィンの活性立体配座の固定による鎮静作用の分離 (2016)
  • Author(s): 谷田誠浩、山本直司、南雲康行、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
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Year and Date: 2016-11-30
• [Presentation] 新規ビシクロ[2.2.2]オクテン骨格を有するκ受容体選択的作動薬の合成と薬理評価 (2016)
  • Author(s): 谷田誠浩、山本直司、南雲康行、長瀬博
  • 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: 北海道大学薬学部（北海道札幌市）
  • Year and Date: 2016-08-19
• [Presentation] Design and Synthesis of κ Opioid Receptor Selective Ligand with a Propellane Skeleton (2016)
  • Author(s): Ryo Nakajima, Naoshi Yamamoto, Shigeto Hirayama, Takashi Iwai, Akiyoshi Saitoh, Yasuyuki Nagumo, Hideaki Fujii, Hiroshi Nagase
  • Organizer: 日本化学会第96春季年会2016
  • Place of Presentation: 同志社大学京田辺キャンパス（京都府京田辺市）
  • Year and Date: 2016-03-24
• [Presentation] Synthesis of novel pentacyclic derivatives with propellane skeleton and their structure-activity relationships (2015)
  • Author(s): Ryo Nakajima, Naoshi Yamamoto, Shigeto Hirayama, Takashi Iwai, Toru Nemoto, Hideaki Fujii, Hiroshi Nagase
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] プロペラン骨格を有する新規五環性化合物の合成とその構造活性相関 (2014)
  • Author(s): 中嶋龍、山本直司、平山重人、岩井孝志、根本徹、藤井秀明、長瀬博
  • Organizer: 第32回メディシナルケミストリーシンポジウム
  • Place of Presentation: 神戸国際会議場（兵庫県、神戸市）
  • Year and Date: 2014-11-26 – 2014-11-28
• [Presentation] プロペラン骨格を有する新規五環性化合物の合成とその構造活性相関 (2014)
  • Author(s): 中嶋龍、山本直司、平山重人、岩井孝志、根本徹、藤井秀明、長瀬博
  • Organizer: 第44回複素環化学討論会
  • Place of Presentation: 札幌市民ホール（北海道、札幌市）
  • Year and Date: 2014-09-10 – 2014-09-12
• [Remarks] http://nagase.wpi-iiis.tsukuba.ac.jp/
• [Remarks] 筑波大学国際統合睡眠医科学研究機構長瀬研究室ホームページ
  • URL: http://nagase.wpi-iiis.tsukuba.ac.jp/research/
• [Patent(Industrial Property Rights)] モルヒナン誘導体 (2017)
  • Inventor(s): 長瀬博、山本直司
  • Industrial Property Rights Holder: 国立大学法人筑波大学、日本ケミファ株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-023444
  • Filing Date: 2017-02-10
• [Patent(Industrial Property Rights)] MORPHINAN DERIVATIVE (2017)
  • Inventor(s): 長瀬博、山本直司
  • Industrial Property Rights Holder: 国立大学法人筑波大学、日本ケミファ株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-03-20
  • Overseas