2000 Fiscal Year Final Research Report Summary
Studies on the development of new opioid agonist by utilizing Mitragyna alkaloids as the lead-compounds
| Project/Area Number |
10557229
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
医薬分子機能学
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| Research Institution | Chiba University |
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Principal Investigator |
TAKAYAMA Hiromitsu Chiba University Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 助教授 (90171561)
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| Co-Investigator(Kenkyū-buntansha) |
HORIE Shunji Chiba University Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 助教授 (50209285)
WATANABE Kazuo Chiba University Faculty of Pharmaceutical Sciences Professor, 薬学部, 名誉教授 (80019124)
AIMI Norio Chiba University Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (30009170)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Mitragyna plant / Mitragynine / Indole alkaloid / Opioid agonist / Analgesic activity / Opioid receptor / Structure-activity relationship |
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| Research Abstract |
1. The leaves of Mitragyna speciosa Korth. (Rubiaceae) have been traditionally used as a substitute for opium in Thai and Malaysia. Reinvestigation of the alkaloidal constituents of the plant in Malaysia resulted in the isolation of new 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids. The structures of the new compounds were elucidated by spectroscopic analysis and total synthesis.
2. A potent opioid agonistic property of mitragynine, a major alkaloid of this plant, have been demonstrated. Based on this finding, more than 30 derivatives of mitragynine were prepared and their activity was evaluated in vitro. Among the compounds, mitragynine pseudoindoxyl and 7-hydroxymitragynine exhibited more potent affinity to (μ-) opioid receptor than that of morphine. Using those results, we investigated the structure-activity relationship to clarify the essential structural moieties for exhibiting the analgesic activity and then proposed a plausible binding model for the interaction mode between the opioid receptor and 7-hydroxymitragynine as a ligand.
3. Further, we found that 7-hydroxymitragynine exhibited strong antinociceptive activity in vivo experiments (s.c. and p.o. administration) in mice, whose potency was far greater than that of morphine. This finding demonstrates that Mitragyna alkaloids or their derivatives could be the promissing lead-compound for the development of useful and practical analgesic agents.
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