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

The mammalian alkaloids tryptoline (1) and eleagnine (2) as well as the highly halogenated (X = F, Cl Br) tetrahydro-beta-carbolines (TH beta Cs) 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-beta-carboline ('TaBro', 5), which was prepared in high yields from the biogenic amine tryptamine ('Ta', 7) and the unnatural aldehyde bromal ('Bro', 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 TH beta Cs 1-5 investigated, intranigral application of a single dose of 10 mu g 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 (IC(50) = 200 CIM) as well as its dehydrohalogenation product 11 (IC(50) = 150 mu M) exhibited the most pronounced inhibitory potential on mitochondrial respiration. The halogen-free TH beta Cs 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(+): IC(50) - 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 TH beta Cs (12-14) revealed the tetrahydropyrido part to adopt a nearly planarized half-chair conformation. Because of the steric demand of the trihalogenmethyl moiety (CF(3) < CCl(3) < CBr(3)), the N-substituent is dramatically pushed out of that ring 'plane'. (C) 2000 Elsevier science Ltd. All rights reserved.