Cytotoxicity of 17 tetrahydroisoquinoline derivatives in SH-SY5Y human neuroblastoma cells is related to mitochondrial NADH–ubiquinone oxidoreductase inhibition

Since the first report that 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine induces parkinsonism, various kinds of low-molecular-weight neurotoxins, such as tetrahydroisoquinoline derivatives, have been identified as possible Parkinson's disease-inducing substances. In the present study, we measured four parameters of 17 tetrahydroisoquinoline derivatives, i.e., cytotoxicity in SH-SY5Y human neuroblastoma cells, inhibitory activity towards mitochondrial NADH–ubiquinone oxidoreductase (complex I), affinity for dopamine transporter, and 1-butanol–H2O partition coefficient (as an index of lipophilicity). Six of the derivatives showed comparatively strong inhibitory activity towards complex I (IC50 values < 100 μM) and five of them were cytotoxic to SH-SY5Y cells (TC50 values < 200 μM). Some of these compounds are endogenous. We found good correlations between cytotoxicity and complex I inhibitory activity, but not between cytotoxicity and affinity for dopamine transporter. Since cytotoxicity to SH-SY5Y neuroblastoma cells was related to inhibitory activity towards mitochondrial complex I, complex I inhibition is likely to be involved, at least in part, in the mechanism of TIQ derivative-induced cell death. Uptake of most of these compounds seems to be dependent on lipophilicity, rather than active transport via dopamine transporter.