Bromal-derived tetrahydro-beta-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 hig hly 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 in ducing a severe impairment of the nigrostriatal dopamine metabolism and inh ibiting complex I of the mitochondrial respiratory chain highly selectively . Within the series of compounds tested, 1-tribromomethyl-1,2,3,4-tetrahydr o-beta-carboline ('TaBro', 5), which was prepared in high yields from the b iogenic amine tryptamine ('Ta', 7) and the unnatural aldehyde bromal ('Bro' , 8) by a Pictet-Spengler cyclization reaction, turned out to be the most p otent toxin in vitro and in vivo. As demonstrated by voltammetric measureme nts on rats, for all the TH beta Cs 1-5 investigated, intranigral applicati on of a single dose of 10 mu g resulted in a significant reduction of the d opaminergic activity in the striatum, with the strongest effect being obser ved for TaBro (5). Using rat brain homogenates, again 5 (IC50 = 200 CIM) as well as its dehydrohalogenation product 11 (IC50 = 150 mu M) exhibited the most pronounced inhibitory potential on mitochondrial respiration. The hal ogen-free TH beta Cs 1 and 2 as well as the MPTP metabolite 1-methyl-4-phen ylpyridinium 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 sy nthesized and tested. An X-ray diffraction study on the 3-dimensional struc ture of trifluoroacetylated highly halogenated TH beta Cs (12-14) revealed the tetrahydropyrido part to adopt a nearly planarized half-chair conformat ion. Because of the steric demand of the trihalogenmethyl moiety (CF3 < CCl 3 < CBr3), the N-substituent is dramatically pushed out of that ring 'plane '. (C) 2000 Elsevier science Ltd. All rights reserved.