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

点击翻译按钮获取中文摘要

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