Discovery of novel mu-delta opioid receptor agonistic analgesics with low analgesic tolerance

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19216
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pain science
• Research Institution: Kitasato University
• Principal Investigator: Hirayama Shigeto 北里大学, 薬学部, 助教 (40565842)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: オピオイド / 鎮痛薬

Outline of Final Research Achievements

We tested the activities of 200 compounds in our compound library for the μ-δ, μ, and δ receptors (ORs). The 80 compounds showed higher activities for the μ-δ OR than ML335, which is a representative μ-δ OR agonist. Furthermore, we evaluated concentration-response relationships for the μ-δ OR of the 9 compounds within the 80 compounds, which showed not only high μ-δ OR activities but also low μ and δ OR activities. As a result, SYK424, SYK555, SYK556, SYK564, and SYK664 exhibited more potencies than ML335. Although we found hit compounds as novel μ-δ OR agonists, we did not complete optimization of the hit compounds and assessment of their antinociceptive effects.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

緩和医療の現場では、モルヒネを含むオピオイド鎮痛薬の長期使用による鎮痛耐性が問題となっており、オピオイドの増量、オピオイドスイッチングおよび鎮痛補助薬の併用にて対応しているものの、治療効果が十分である例は必ずしも多くない。先行研究よりμ-δ受容体作動薬が鎮痛耐性を形成しない強力な鎮痛薬になり得ることが示されており、本研究で見出された強力なμ-δ受容体作動薬は現状のオピオイド鎮痛薬の問題点の1つを解決する一助になり得ると考えられる。