Construction of morphinan-based focused library

2023 Fiscal Year Final Research Report

• Project Area: Multi-scale platform for untangling physiological complexity
• Project/Area Number: 21H05115
• Research Category: Grant-in-Aid for Transformative Research Areas (B)
• Allocation Type: Single-year Grants
• Review Section: Transformative Research Areas, Section (II)
• Research Institution: University of Tsukuba
• Principal Investigator: Saitoh Tsuyoshi 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80609933)
• Co-Investigator(Kenkyū-buntansha): 南雲 康行 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (00459661)
• Project Period (FY): 2021-08-23 – 2024-03-31
• Keywords: オピオイド受容体 / Gタンパク質共役型受容体 / シグナル伝達 / 分子設計 / κオピオイド受容体 / δオピオイド受容体

Outline of Final Research Achievements

This study aimed to elucidate the structural factors of ligands and receptors linked to the physiological actions of GPCRs. Using κ and δ opioid receptors as model systems, a diverse array of ligands was constructed through organic synthetic transformations of the morphinan skeleton. These ligands were then analyzed for their intracellular signaling profiles and pharmacological effects in mice. The results revealed that specific structural factors altered β-arrestin signaling. Moreover, the identified G protein-biased KOR ligands demonstrated significant analgesic effects while markedly reducing sedative side effects in in vivo evaluations. This suggests that side effects in KOR may be attributed to β-arrestin signaling. These findings contribute to the development of novel analgesics targeting opioid receptors, offering effective pain relief with minimized adverse effects.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

本研究は、オピオイド受容体を標的とする医薬における副作用のメカニズムをマルチスケールで解明し、副作用を抑えた鎮痛薬の開発に繋がる意義がある。特に、Gタンパク質バイアス型KORリガンドは、副作用を低減しつつ鎮痛効果を持続させる新しい治療法を提供する可能性があることが示された。これにより、慢性痛や癌痛などで苦しむ患者の生活の質を向上させ、医療現場での薬物治療の安全性と有効性を高めることが期待される。