Development of anti-Parkinson's disease drugs using P-glycoprotein knockout mice heated with endogenous neurotoxin.

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The purpose of this research is to find anti-Parkinson's disease agent from 1-methyl-tetrahydroisoquinoline derivatives. Hydroxy derivatives have high effect, but they are difficult to penetrate of blood-brain barrier, because of their water solubility.The ester group was introduced to the hydroxylated 1-methyl tetrahydroisoquinoline derivatives. They had better anti-parkinsonism effect than hydroxyl derivatives. The second purpose of this study is the examination of the relationship between parkinsonism and the transport characteristics (influx/outflux) of tetrahydroisoquinolines across the blood-brain barrier. At first, to examine the substrate specificity of tetrahydroisoquinolines as P-glycoprotein (P-gp) substrates.These results indicate that 3',4'DHBnTIQ, an endogenous parkinsonism-inducing neurotoxin, is a P-gp substrate.These results may also suggest that P-gp inactivation and/or dysfunction in the brain are closely related to the induction of Parkinson's disease.