Development of non-steroidal anti-inflammatory analgesics which have TRP channel antagonism effect

• Project/Area Number: 16K08334
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Shujitsu University
• Principal Investigator: Yamakawa Naoki 就実大学, 薬学部, 准教授 (20583040)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 医薬品探索 / 非ステロイド系抗炎症薬 / 抗炎症薬 / 鎮痛薬 / 非ステロイド性抗炎症薬 / NSAIDs

Outline of Final Research Achievements

The purpose of this study was to search the NSAIDs involved in the activation of the TRP channel and to investigate the possibility about the creation of a new type of analgesics. The analgesic effect by test compound was carried out using a rat pain models, and the direct action against the TRP channel was analyzed using electrophysiological technique. Several derivatives which modified an aromatic ring of known NSAIDs inhibit significantly both non-inflammatory and inflammatory pain. The result suggested that these ligands activate the ion channels which belong to TRPA or TRPV family.

Academic Significance and Societal Importance of the Research Achievements

鎮痛薬は日常生活のみならず、歯科治療後の痛みや外科手術後の疼痛、さらには緩和医療に至るまで様々な局面で使用される。本研究は、NSAIDのイオンチャネルとの関わりを解明し、強力かつ即効性のある新しいタイプの鎮痛薬の合成を目指す研究である。研究期間内に得られた成果は、NSAIDが新たな標的（TRPチャネル）を介して疼痛作用をもたらすといった学術的に興味深い知見であり、医薬品開発に直結する点においても社会的貢献性が極めて高いと考えられる。

Research Products

• [Journal Article] Antinociception by fluoro-loxoprofen, a novel non-steroidal anti-inflammatory drug with less ulcerogenic effects, in rat models of inflammatory pain (2019)
  • Author(s): Asano Teita、Hattori Tomoki、Tanaka Ken-ichiro、Yamakawa Naoki、Suemasu Shintaro、Aida Shuji、Kataoka Marika、Mizushima Tohru、Takenaga Mitsuko
  • Journal Title: European Journal of Pharmacology Volume: 844 Pages: 253-258
  • DOI: 10.1016/j.ejphar.2018.12.008
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Mepenzolate Derivatives With Long-Acting Bronchodilatory Activity (2018)
  • Author(s): Yamakawa Naoki and Tanaka Ken-Ichiro、Yamashita Yasunobu、Asano Teita、Kanda Yuki、Takafuji Ayaka、Kawahara Masahiro、Takenaga Mitsuko、Fukunishi Yoshifumi、Mizushima Tohru
  • Journal Title: Frontiers in Pharmacology Volume: 9
  • DOI: 10.3389/fphar.2018.00344
  • Peer Reviewed / Open Access
• [Presentation] フルオロロキソプロフェン異性体の合成と薬理活性の評価 (2018)
  • Author(s): 杉本早紀、浅野帝太、山川 直樹
  • Organizer: 日本薬学会第138年会
• [Presentation] Cytotoxic effects of aspirin derivatives modified with halogen. (2018)
  • Author(s): Yamakawa N and Katsu T
  • Organizer: ASEAN-JAPAN Genome Medicine Reserch Promotion Conference
  • Int'l Joint Research
• [Presentation] ハロゲン修飾されたアスピリン誘導体の膜傷害作用 (2017)
  • Author(s): 橋本千聡、谷田滉季、山川直樹
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2017-03-24
• [Presentation] Evaluation of the Membrane Permeabilizing Activity of Aspirin derivatives Modified with Halogen. (2017)
  • Author(s): Yamakawa N
  • Organizer: The 8th International Meeting on Halogen Chemistry
  • Int'l Joint Research
• [Presentation] ロキソプロフェンを基盤としたCOX－2阻害薬の創製 (2016)
  • Author(s): 山川 直樹、勝孝、大塚雅巳、水島徹
  • 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
  • Year and Date: 2016-11-30