Development of novel, specific heterodimerized opioid agonists with less tolerance and side effects

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Jikei University School of Medicine (2020); National Cancer Center Japan (2018-2019)
• Principal Investigator: Uezono Yasuhito 東京慈恵会医科大学, 医学部, 教授 (20213340)
• Co-Investigator(Kenkyū-buntansha): 宮野 加奈子 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 (50597888)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: オピオイド受容体 / GPCR / 二量体 / オピオイド耐性 / μ/δヘテロマー

Outline of Final Research Achievements

Recent progress has shown that agonists for dimerized opioid μ/δ receptors formed by μ and δ receptors are less likely to cause tolerance and side effects. The principal investigator synthesized novel prospective μ/δ compounds and screened them as μ/δ dimer-selective agonists. As a result, we were able to identify four selective agonists with high affinity for μ/δ dimerized receptors but low affinity for μ and δ receptors. Furthermore, ten of new compounds have also been constructed by using four agonists as lead compounds. In the future, by using these candidates, we will conduct animal experiments and carry out for licensing out of optimized compounds to pharmaceutical companies to launch next novel opioids with less side effects.

Free Research Field

疼痛学

Academic Significance and Societal Importance of the Research Achievements

がんの痛みの軽減等に広く用いられている医療用オピオイド麻薬は副作用が必発であるため、副作用の少ない新規オピオイド製剤の開発が求められている。オピオイドμおよびδ受容体からなる二量体化受容体のアゴニストが副作用の少ないオピオイド製剤となるという基礎研究を元に、現在世界中でμ/δ二量体特異的アゴニストの開発が行われている。今回の研究において、オピオイドμ/δ二量体受容体特異的アゴニストを複数合成することができた。同アゴニストを企業導出することで新規オピオイド製剤の開発の道が開けると信じる。