Studies on the development of new opioid agonist by utilizing Mitragyna alkaloids as the lead-compounds

1.大花铁线菊叶。在泰国和马来西亚，(茜草科)传统上被用作鸦片的替代品。通过对马来西亚产该植物生物碱成分的重新研究，分离得到新的9-甲氧基-Corynanthe型单萜吲哚生物碱。新化合物的结构经波谱分析和全合成确证。该植物的一种主要生物碱--米拉吉宁具有很强的阿片类激动剂活性。基于这一发现，合成了30多个三叶草碱的衍生物，并对它们的体外活性进行了评价。与吗啡相比，三氢呋喃类化合物对(μ-)阿片受体具有更强的亲和力。利用这些结果，我们研究了阿片受体的构效关系，阐明了阿片受体显示镇痛活性的基本结构单元，并提出了阿片受体与7-羟基米曲布宁相互作用模式的合理结合模型。此外，我们在活体实验中发现7-羟基三氮杂环氨酸具有很强的抗伤害性作用(S.C.和邮政总局。在小鼠体内)，其效力远远大于吗啡。这一发现表明，三叶草生物碱或其衍生物可能是开发实用止痛药的有希望的先导化合物。

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.