Bromal-derived tetrahydro-β-carbolines as neurotoxic agents: chemistry, impairment of the dopamine metabolism, and inhibitory effects on mitochondrial respiration Original Research Article

The mammalian alkaloids tryptoline (1) and eleagnine (2) as well as the highly halogenated (X=F, Cl, Br) tetrahydro-β-carbolines (THβCs) 3–5, structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 6), were found to have a common feature of inducing a severe impairment of the nigrostriatal dopamine metabolism and inhibiting complex I of the mitochondrial respiratory chain highly selectively. Within the series of compounds tested, 1-tribromomethyl-1,2,3,4-tetrahydro-β-carboline (‘TaBroʹ, 5), which was prepared in high yields from the biogenic amine tryptamine (‘Taʹ, 7) and the unnatural aldehyde bromal (‘Broʹ, 8) by a Pictet–Spengler cyclization reaction, turned out to be the most potent toxin in vitro and in vivo. As demonstrated by voltammetric measurements on rats, for all the THβCs 1–5 investigated, intranigral application of a single dose of 10 μg resulted in a significant reduction of the dopaminergic activity in the striatum, with the strongest effect being observed for TaBro (5). Using rat brain homogenates, again 5 (IC50=200 μM) as well as its dehydrohalogenation product 11 (IC50=150 μM) exhibited the most pronounced inhibitory potential on mitochondrial respiration. The halogen-free THβCs 1 and 2 as well as the MPTP metabolite 1-methyl-4-phenylpyridinium ion (MPP+), by contrast, showed only a moderate inhibition at concentrations in the millimolar range (e.g. for MPP+: IC50=3.5 mM). For an elucidation of the role of hydrophobic portion in the inhibitory action against complex I activity, several N-acyl derivatives (15–21) of 5 were synthesized and tested. An X-ray diffraction study on the 3-dimensional structure of trifluoroacetylated highly halogenated THβCs (12–14) revealed the tetrahydropyrido part to adopt a nearly planarized half-chair conformation. Because of the steric demand of the trihalogenmethyl moiety (CF3