Preventative effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives ( N -functional group loading) on MPTP-induced parkinsonism in mice.

1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ (1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQ derivatives (loading an N -propyl, N -propenyl, N -propargyl, or N -butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like signs in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me- N -propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me- N -propargyl-TIQ and 1-Me- N -butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQ and 1-Me- N -propyl-TIQ did not. These results suggest that although loading an N -propargyl group on 1-MeTIQ clearly enhanced neuroprotective effects, other N -functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N -functional group may contribute to the observed differences in effect.