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

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，采用Pummere型环合反应，经7步反应制得1-苄基-1，2，3，4-四氢异喹啉（1-BnTIQ），总收率为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

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