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

Abstract 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 (‘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 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 (IC 50 =200 μM) as well as its dehydrohalogenation product 11 (IC 50 =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 + : 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 THβCs ( 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 3 3 ), the N -substituent is dramatically pushed out of that ring ‘plane'.