TACLO AS A NEUROTOXIC LEAD - IMPROVED SYNTHESIS, STEREOCHEMICAL ANALYSIS, AND INHIBITION OF THE MITOCHONDRIAL RESPIRATORY-CHAIN

''TaClo'', a highly halogenated tetrahydro-beta-carboline derived from the biogenic amine tryptamine (''Ta'') and the synthetic hypnotic chl oral (''Clo''), has to be considered as a dopaminergic neurotoxin pote ntially occurring in vivo. For the preparation of TaClo on a large sca le, an improved synthetic pathway was elaborated. The distinct neuroto xic activity of TaClo warrants its intensive study also under stereoch emical aspects. For this reason, an analytic device for the separation and stereochemical attribution of its two enantiomers, (R)-TaClo and (S)-TaClo, was developed, based on chromatography on a chiral HPLC pha se. Elucidation of the absolute configuration was achieved by CD spect roscopy and confirmed by X-ray crystallography. TaClo exhibits highly selective in vitro inhibition of complex I of the mitochondrial respir atory chain, the required concentrations being much lower than those n eeded for related halogen-free beta-carbolines or for MPP(+) (1-methyl -4-phenyl-pyridinium ion), the active metabolite of MPTP (1-methyl-4-p henyl-1,2,3,6-tetrahydropyridine). Furthermore, TaClo as a novel lead structure stimulated chemical and neuropharmacological investigations also on related highly halogenated beta-carbolines. Thus, some of the tested compounds - both potential TaClo metabolites and unnatural deri vatives - showed even an enhanced inhibition of the mitochondrial resp iration in vitro.