Synthesis and neuroprotection of endogenous brain amine, tetrahydroisoquinoline derivatives for experimental parkinson 's animals

内源性脑胺、四氢异喹啉衍生物的合成及其对实验性帕金森病动物的神经保护作用

• 批准号: 13672301
• 负责人: TAGUCHI Kyoji
• 金额: $ 2.18万
• 依托单位: Showa Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672301/
• 关键词: Anti-Parkinson drugs; 1,2.3.4-tetrahydroisoquinoline; 1-methyl-1,2,3,4- tetrahydroisoquinoline; 1.2.3.4-tetrahydroisoquinoline; Dopamine; 1-benzyl-1.2.3,4-tetrahydroisoquinoline; C57BL; 6N; Mouse; 黒質ドパミン神経細胞; 1-methyll-1,2,3,4-tetrahydroisoquino

We carried out behavioral, pathological and biochemical studies in C57BL/6N mice in order to determine whether the stereo-structure of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ), an endogenous amine present as a mixture of (R)- and (S)-enantiomers, affects the onset of Parkinson's disease-like symptoms, which are induced by 1,2,3,4-tetrahydroisoquinoline (TIQ) in mice. An improved synthesis of (R)- and (S)-1-MeTIQ was achieved via the acid induced Pummere-type cyclization of chiral N-[1-methyl-2- (phenylsulfinyl)ethyl]-N-(1-phenylethyl)formamid as a key step, starting from commercially available (R)- and (S)-benzylamine required 6 steps in about 48% total yield. 1-benzyl-1,2,3,4- tetrahydroisoquinoline (1-BnTIQ) was prepared from benzophenone in 7 steps using Pummere-type cyclization in 55% total yield. These results demonstrated that the Pummere-type cyclization of sulfoxide provides a efficient method of synthesizing of various substituted TIQs. (R)-1-MeTIQ, and not (S)- enant … More iomer, plays a crucial role in the protection of TIQ-induced parkinsonism, a fact which suggests that enantiomeric biochemical events such as 1-MeTIQ biosynthesis may participate in the pathogenesis of PD. TIQ analogs profoundly stimulated dopamine release which resulted in the competitive inhibition of the binding of [11C]raclopride to dopamine D2 receptors, but did not induce degeneration of the receptors. Next, we administered 1-BnTIQ, an endogenous neurotoxin known to cause bradykinesia, the Parkinson's disease-like symptoms, in order to obtain biochemical and pathological evidence of behavioral abnormalities. 1-BnTIQ-induced bradykinesia has a different mechanism of action than that underlying the MPTP-induced depletion of striatal DA neurons, that 1-BnTIQ does not affect the density of DATs on dopaminergic neurons. TIQ-induced parkinsonism model is different from the MPTP-induced model as evaluated by the radioligand-DATs binding and that (S)- 1-MeTIQ has a preventing effect for the degeneration of the DATs to a certain extent. Less

我们在C57 BL/6 N小鼠中进行了行为、病理和生化研究，以确定1-甲基-1，2，3，4-四氢异喹啉（1-MeTIQ）（一种以（R）-和（S）-对映体的混合物存在的内源性胺）的立体结构是否影响小鼠中由1，2，3，4-四氢异喹啉（TIQ）诱导的帕金森病样症状的发作。以手性N-[1-甲基-2-（苯亚磺酰基）乙基]-N-（1-苯乙基）甲酰胺为原料，经酸诱导的Pummere型环化反应合成了（R）-和（S）-1-MeTIQ，总收率约48%。以二苯甲酮为原料，经Pummere环合反应，经7步反应制得1-苄基-1，2，3，4-四氢异喹啉（1-BnTIQ），总收率55%。这些结果表明，亚砜的Pummere型环化反应提供了一种合成各种取代TIQ的有效方法。（R）-1-MeTIQ，而不是（S）-对映体 ...更多信息 在保护TIQ诱导的帕金森综合征中起着至关重要的作用，这一事实表明对映体生物化学事件如1-MeTIQ生物合成可能参与PD的发病机制。TIQ类似物深刻刺激多巴胺释放，导致[11 C]雷氯必利与多巴胺D2受体结合的竞争性抑制，但不诱导受体变性。接下来，我们给予1-BnTIQ，一种已知会引起运动迟缓（帕金森病样症状）的内源性神经毒素，以获得行为异常的生化和病理学证据。1-BnTIQ诱导的运动迟缓与MPTP诱导的纹状体DA神经元耗竭的作用机制不同，1-BnTIQ不影响多巴胺能神经元上的DAT密度。TIQ诱导的帕金森病模型与MPTP诱导的模型不同，通过放射性配体-DAT结合评价，并且（S）-1-MeTIQ在一定程度上对DAT的变性具有预防作用。少

项目成果

Kiichi Ishikawa, Yasuhiro Koyanagi, Kenji Abe, Kazunori Kawamura,Kyoji Taguchi, Toshiaki Saitoh, Jun Toda and Takehiro Sano.: "Effects of single and repeated administration of 1,2,3,4-tetrahydroisoquinoline analogs on the binding of [11C]racloprode to dop

Kiichi Ishikawa、Yasuhiro Koyanagi、Kenji Abe、Kazunori Kawamura、Kyoji Taguchi、Toshiaki Saitoh、Jun Toda 和 Takehiro Sano.：“单次和重复施用 1,2,3,4-四氢异喹啉类似物对 [11C] 结合的影响

Kiichi Ishikawa et al.: "Effects of single and repeated administration of 1,2,3,4-tetrahydroisoquinoline analogs on the binding of [11C]racloprode to dopamine D2 receptors in the mouse brain"Journal of Neuronal Transmission. 108. 1111-1125 (2001)

Kiichi Ishikawa 等人：“单次和重复施用 1,2,3,4-四氢异喹啉类似物对 [11C]雷氯普罗德与小鼠大脑中多巴胺 D2 受体结合的影响”神经传递杂志。

Kiichi Ishiwata et al.: "No reduction of dopamine transporter binding sites in mice following treatment with the TIQ analogue 1-benzyl-1,2,3,4-tetrahydroisoquinoline"Brain Research. 960. 282-285 (2003)

Kiichi Ishiwata 等人：“用 TIQ 类似物 1-苄基-1,2,3,4-四氢异喹啉治疗后，小鼠多巴胺转运蛋白结合位点没有减少”大脑研究。

Kenji Abe, Kyoji Taguchi, Tomoko Wasai, Jin Ren, Iku Utsunomiya,Tatsumi Shinohara, Tadashi Miyatake and Takehiro Sano.: "Biochemical and pathological study of endogenous 1 - benzyl - 1,2,3,4 -tetrahydroisoquinoline -induced parkinsonism in the mouse."Brai

Kenji Abe、Kyoji Taguchi、Tomoko Wasai、Jin Ren、Iku Utsunomiya、Tatsumi Shinohara、Tadashi Miyatake 和 Takehiro Sano.：“内源性 1 - 苄基 - 1,2,3,4 -四氢异喹啉诱发的帕金森症的生化和病理学研究

Kiichi Ishikawa, Yasuhiro Koyanagi, Kenji Abe, Kazunori Kawamura, Toshiaki Saitoh, Kyoji Taguchi, Jun Toda, Michio Senda and Takehiro Sano.: "Evaluation of neurotoxicity of TIQ and MPTP and of parkinsonism-preventing effect of 1-MeTIQ by in vivo measureme

Kiichi Ishikawa、Yasuhiro Koyanagi、Kenji Abe、Kazunori Kawamura、Toshiaki Saitoh、Kyoji Taguchi、Jun Toda、Michio Senda 和 Takehiro Sano.：“通过体内测量评估 TIQ 和 MPTP 的神经毒性以及 1-MeTIQ 的帕金森症预防效果