Medicinal Chemistry on Indole Alkaloids from Thai Medicinal Plants

泰国药用植物吲哚生物碱的药物化学

• 批准号: 06044035
• 负责人: SAKAI Shin-ichiro
• 金额: $ 10.69万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06044035/
• 关键词: Thai medicinal plant; Mitragyna speciosa; indole alkaloid; mitragynine; analgesic effect; serotonin receptor; opioid receptor; Ca channel; 平滑筋収縮作用; アルカロイド化学合成; オピオイド作用; Hunteria zeylanica; Rauwolfia sumatorana; アルカロイドの化学合成

Mitragyna speciosa (Korth.) Havil., endemic to Malyasia and Thailand, is a species of particular medicinal importance. In these countries the leaves of this plant have been traditionally used such as a remedy as a stimulant, an anthelminic, a substitute for opium, an antidiarrheal or to relieve muscular pain. Phytochemical studies on the constituents of the plant growing in Thailand as well as in Malaysia have lead to isolation and identification of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids. The first total synthesis of (-) -mitragynine (MG), the major component of this plant, was achieved in the optically pure form using an enantiomerically and stereochemically convergent route. Furthermore, the oxindole and pseudoindoxyl derivatives of mitragynine were prepared. Pharmacological evaluation of these natural and syntheic compounds was performed, which have lead to the following significant results. MG suppressed 5-HT2A receptor-mediated head-twitch responses in mi … More ce. This suppressive effect was antagonized by an alpha2-adrenoceptor antagonist, but not by noradrenaline- or 5-HT-depletors, suggesting that stimulation of postsynaptic alpha2-adrenoceptors and/or blockade of 5-HT2A receptors are involved in MG suppression of head-twitch responses. MG produced antinociception in the tail-pinch test in mice. MG-induced antinociception was attenuated not only by naloxone, an opioid antagonist, but also by alpha2-or5-HT-receptor antagonists. These results suggest that supraspinal opioid systems and descending monoaminergic systems play roles in antinociceptive activity of supraspinally administered MG on the mechanical noxious stimulation. Effects of MG on neurogenic contraction of vas deference and ileum were studied. MG inhibited neurotransmitter release from nerve endings, leading to inhibition of neurogenic contraction in vas deference. By using the patch clamp and the Ca fluorescent dye methods, MG was found to block L-and T-type Ca channel currents in neuronal cells. In the ileum, MG and mitragynine pseudoindoxyl (MGP) inhibited the neurogenic contraction through the stimulation of opioid mu-receptors. The opioid effects of MG and MGP were about 0.2-and 20-fold activity of morphine, respectively. These neuronal Ca channel blocking-and opioid-effects may be involved in the analgesic effect of MG. Less

光叶水母Mitrigyna orosa(Korth.)哈维尔，马利亚和泰国特有，是一种具有特殊药用价值的物种。在这些国家，这种植物的叶子传统上被用作兴奋剂、驱虫药、鸦片替代品、止泻药或缓解肌肉疼痛。对生长在泰国和马来西亚的植物的化学成分进行了研究，分离和鉴定了几种9-甲氧基-Corynanthe型单萜吲哚生物碱。该植物的主要成分(-)-硝基呋喃(MG)的首次全合成是利用对映体和立体化学会聚的方法以光学纯的形式实现的。此外，还合成了三氢呋喃的氧化吲哚和拟吲哚衍生物。对这些天然和人工合成的化合物进行了药理评价，得到了以下重要结果。MG抑制5-HT2A型受体介导的小鼠…甩头反应更多的CE。这种抑制作用可被α2肾上腺素受体拮抗剂所拮抗，但不能被去甲肾上腺素或5羟色胺耗竭剂所拮抗，这表明刺激突触后α2肾上腺素受体和/或阻断5 HT2a受体参与了MG抑制头部抽动反应。在小鼠夹尾痛实验中，镁具有抗伤害作用。阿片类拮抗剂纳洛酮和α2-或5-羟色胺受体拮抗剂均可减弱镁的抗伤害性作用。这些结果提示，脊髓上阿片系统和下行单胺系统参与了脊髓上注射MG对机械伤害性刺激的抗伤害性作用。研究MG对输精管和回肠神经性收缩的影响。镁可抑制神经末梢的神经递质释放，从而抑制血管的神经源性收缩。应用膜片钳和钙荧光染料方法，发现MG可阻断神经元细胞的L和T型钙通道电流。在回肠，MG和MGP通过阿片Mu受体的兴奋抑制神经源性收缩。MG和MGP的阿片作用分别是吗啡的0.2倍和20倍。这些神经元钙通道阻断和阿片类药物效应可能参与了MG的镇痛作用。较少

项目成果

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H.Takayama：“新型二吲哚生物碱，11-甲氧基凝胶半酰胺的仿生合成”四面体。

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P.奥比茨：爱思唯尔。

H.Takayama: "Fist Synthesis of the Novel Gelsemium Alkaloids,Gelselegine,Gelsenicine,and Gelsedine Using a Biomimetic Approach." J.Org.Chem.59. 4381-4385 (1994)

H.Takayama：“利用仿生方法首次合成新型钩吻生物碱、钩吻碱、钩吻碱和钩吻碱。”

S.Yano: "Pharmacolagical Features of Non-adrenergic Non-cholinergic (NANC) Relaxation Induced by Eletrical Vagal Stimulation in Isolated Mouse Stomach." Jpn.J.Pharmacol.69. 9-15 (1995)

S.Yano：“离体小鼠胃中迷走神经电刺激诱导的非肾上腺素能非胆碱能 (NANC) 松弛的药理学特征。”

W.Reanmongkol: "Antinocicetive and Antipyretic Effects of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica." Biol.Pharm.Bull.17. 1345-1350 (1994)

W.Reanmongkol：“从Hunteria zeylanica 茎皮中提取的生物碱的镇痛和解热作用。”