Development of anti-parkinsonism agent related to endogenous amines as pharmacophore

内源性胺类药效团抗帕金森病药物的研制

• 批准号: 03557094
• 负责人: HIROBE Masaaki
• 金额: $ 6.27万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03557094/
• 关键词: Parkinson's Disease; Anti-parkinsonism agent; Tetrahydroisoquinoline derivatives; パ-キンソン病; 抗パ-キンソン病薬

It has been known for about 5 years that tetrahydroisoquinoline(TIQ) derivatives may be related to the onset of parkinsonism. TIQ and 1-methyi-1, 2, 3, 4- tetrahydroisoquinoline (1MeTIQ) are endogenous amines coexisting in the brain of many species including humans. Mareover, 1MeTIQ has a preventive effect against parkinsonism in mice.Methyl derivative of TIQs were synthesized in preparative scale. And these pharmacological effects were investigated. From the structure-activity relationship, a methyl group attached 1 position is contributed to locomotive activity. The number of methyl groups is affected toxicity. These findings will be useful for further investigation to find out anti-parkinsonism agents.On the way of the investigation, we found that 1-benzyl-TIQ (1BnTIQ) had very strong neurotoxic character. This compound was also an endogeneous amine in human brain. The content of 1-BnTIQ in parkinsonians is higher than control subjects. So from these data, 1BnTIQ is a very suitable candidate for parkinsonism causing substance.

四氢异喹啉（TIQ）衍生物可能与帕金森综合征的发病有关，这一点已被发现约5年。TIQ和1-甲基-1，2，3，4-四氢异喹啉（1-methyl-1，2，3，4- tetrahydroisoquinoline，1 MeTIQ）是共存于包括人类在内的许多物种脑内的内源性胺。此外，1 MeTIQ对小鼠帕金森病有预防作用。并对其药理作用进行了研究。从构效关系来看，1位甲基对活性有贡献。甲基的数量影响毒性。在研究过程中发现1-苄基-TIQ（1-benzyl-TIQ，1BnTIQ）具有很强的神经毒性。该化合物也是人脑中的内源性胺。帕金森病患者1-BnTIQ含量高于对照组。因此，从这些数据来看，1BnTIQ是一种非常合适的帕金森病致病物质的候选者。

项目成果

M.Tateyama, S.Ohta, T.Nagao, M.Hirobe, H.Ono.: "Effect of 4-phenyl-1, 2, 3, 4-tetrahydroisoquinoline on ambulation induced by injection of methamphetamine into the nucleus accumbens in rats." Neuropharmacology. 32. 243-248 (1993)

M.Tateyama、S.Ohta、T.Nagao、M.Hirobe、H.Ono.：“4-苯基-1,2,3,4-四氢异喹啉对大鼠伏隔核注射甲基苯丙胺诱导的行走的影响

M.Tateyama: "4-phenyl tetrahydroisoquinoline,but not nomifensine or cocaine,inhibits methamptetamine-induced dopamine release." Eur.J.Pharmacol.240. 51-56 (1993)

M.Tateyama：“4-苯基四氢异喹啉，但不是诺米芬辛或可卡因，可以抑制甲基苯丙胺诱导的多巴胺释放。”

H.Nakagawa: "A novel metabolite of 3,4-methylenedioxyamphetamine(MDA):formation of 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and its pharmacological" Biol.Pharm.Bull.16. 579-582 (1993)

H.Nakakawa：“3,4-亚甲基二氧基苯丙胺（MDA）的新型代谢物：3-甲基-6,7-亚甲基二氧基-1,2,3,4-四氢异喹啉的形成及其药理学”Biol.Pharm.Bull.16

H.Nakagawa, Y.Makino, Y.Yoshida, S.Ohta, M.Hirobe.: "A novel metabolite of 3, 4-methylenedioxyamphetamine (MDA) : formation of 3-methyl-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline and its pharmacological effect." Biol.Pharm.Bull.16. 579-582 (199

H.Nakakawa、Y.Makino、Y.Yoshida、S.Ohta、M.Hirobe.：“3, 4-亚甲二氧基苯丙胺 (MDA) 的新型代谢物：3-甲基-6, 7-亚甲二氧基-1, 2 的形成