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

以帽柱生物碱为先导化合物开发新型阿片受体激动剂的研究

• 批准号: 10557229
• 负责人: TAKAYAMA Hiromitsu
• 金额: $ 4.93万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557229/
• 关键词: Mitragyna plant; Mitragynine; Indole alkaloid; Opioid agonist; Analgesic activity; Opioid receptor; Structure-activity relationship

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.

1.紫穗槐的叶子。在泰国和马来西亚，茜草科（Rubiaceae）传统上被用作鸦片的替代品。重新调查的植物中的生物碱成分在马来西亚导致新的9-甲氧基-Corynanthe型单萜吲哚生物碱的分离。新化合物的结构经波谱分析和全合成确证.一个有效的阿片激动剂的属性，这种植物的主要生物碱，已被证明。在此基础上，我们合成了30多个mitragynine衍生物，并对其进行了体外活性评价。在这些化合物中，mitragynine pseudoindoxyl和7-hydroxymitragynine表现出比吗啡更强的（μ-）阿片受体亲和力。利用这些结果，我们研究了构效关系，以澄清显示镇痛活性的必要结构部分，然后提出了阿片受体与7-羟基mitragynine作为配体之间相互作用模式的合理结合模型.此外，我们发现7-羟基mitragynine在体内实验中表现出强的抗伤害活性（s.c.和p.o.给药），其效力远远大于吗啡。这一发现表明，Mitragyna生物碱或其衍生物可能是开发有用和实用的镇痛剂的有希望的先导化合物。

项目成果

H.Takayama: "Structure Revision of Mitragynaline, an Indole Alkaloid in Mitragyna speciosa."Tetrahedron Lett.. 42 (9). 1741-1743 (2001)

H.Takayama：“帽柱木碱（Mitragynaline）的结构修订，帽柱木碱是一种美丽帽柱木中的吲哚生物碱。”Tetrahedron Lett.. 42 (9)。

H.Takayama: "Isolation and Asymmetric Total Synthesis of a New Mitragyna Indole Alkaloid, Mitralactonine."J.Org.Chem.. 64 (6). 1772-1773 (1999)

H.Takayama：“一种新的帽柱吲哚生物碱 Mitralactonine 的分离和不对称全合成。”J.Org.Chem. 64 (6)。

S.Thongpradichote: "Identification of Opioid Receptor, Subtypes in Antinociceptive Actions of Supraspinally-Administered Mitragynine in Mice."Life Sciences. 62. 1371-1378 (1998)

S.Thongpradichote：“阿片受体的鉴定，小鼠脊髓上给药帽柱木碱的镇痛作用亚型。”生命科学。

K.Watanabe: "Pharmacological Properties of Some Structurally Related Indole Alkaloids Contained in the Asian Herbal Medicines, Hirsutine and Mitragynine, with Special Reference to their Ca_<2+> Antagonistic and Opioid-Like Effects.""Pharmacological Resear

K.Watanabe：“亚洲草药、水草碱和帽柱木碱中含有的一些结构相关的吲哚生物碱的药理学特性，特别是它们的 Ca_<2> 拮抗作用和阿片样作用。”“药理学研究

Suchitra Thongpradichote: "Identification of opioid receptor subtypes in antinociceptive actions of supra-spinally-odministered mitragynine in mice" Life Science. 62・16. 1371-1378 (1998)

Suchitra Thongpradichote：“小鼠脊髓上给药帽柱木碱的镇痛作用中阿片受体亚型的鉴定”生命科学 62・16 (1998)。