Highly Halogenated Tetrahydro-β-Carbolines as a New Class of Dopaminergic Neurotoxins

Identification of the Dopaminergic Neurotoxin 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline in Human Blood after Intake of the Hypnotic Chloral Hydrate

“…IR spectra were taken on a Perkin-Elmer 1420 IR spectrometer (Perkin-Elmer, Norwalk, CT), mass spectra were determined on a MAT 8200 (Finnigan MAT, San José, CA) mass spectrometer, and the microanalyses were performed on a Carlo Erba 1106 apparatus (Carlo Erba, Milan, Italy). (6) TaClo (3). According to a procedure described in previous papers (3,6), 3 was synthesized via its formamide by refluxing tryptamine (1) and chloral (2b) in formic acid.…”

“…1) (3) might be formed in mammalian organisms (4 -6). Indeed, this tricyclic indole derivative 3, named TaClo 3 (4), was shown to readily originate in rats treated chronically with small doses of both of its putative precursors, the biogenic amine tryptamine (Ta, 1) and chloral (Clo, 2b) (5). Hence, TaClo (3) might also occur in humans, whenever 2b is incorporated, i.e., by uptake of the soporific 2a, and by exposure (at work) or by addiction to the widely used industrial solvent trichloroethylene (tri, 5), which is known to be metabolized to chloral (2b) (7).…”

Chemical Modification of the Mitochondrial Complex I Inhibitor 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline: Synthesis and Evaluation of N-Alkanoyl Derivatives

“…The parent compound TaClo (2) itself, by contrast, is also able to partially inhibit complex II / III (30% at 500 [am) (Janetzky et al, 1999). As far as we know, also some other TaClo derivatives among them N-alkyl compounds pos sess this inhibitory potential, too (Bringmann et al, 1998). None of these agents was observed to inhibit complex IV.…”

“…Organic solvents were dried and distilled prior to use. 1-Trichloromethyl-1,2,3,4-tetrahydro-9//-pyrido-[3,4-£]indole hydrochloride (2-HC1) was prepared from tryptamine and trichloroacetaldehyde via its /V-formyl derivative 3 as described previously (Bringmann and Hille, 1990;Bringmann et al, 1998). l-Methyl-l,2,3,4-tetrahydro-9//-pyrido[3,4-fr]indole (eleagnine, 10) and l-trichloromethyl-2-trifluoroacetyl-l,2,3,4-tetrahydro-9//-pyrido[3,4-b]indole (13) were synthesized as reported earlier (Bringmann et al, 2000b).…”

“…Since exposure to l-methyl-4-phenylpyridinium ion (MPP+), the bioactive metabolite of the parkin sonism-inducing agent l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP, 1) turned out to cause a selective reduction of complex I activity (Nicklas et al, 1985;Mizuno et al, 1987), compounds struc turally similar to 1, among them isoquinolines and ß-carbolines, have been investigated more closely Our special interest is focussed on 1-trichloromethyl-l,2,3,4-tetrahydro-ß-carboline (TaClo, 2) (see Fig. 1), a progressively-acting neurotoxin (for reviews see Sontag et al, 1996;Bringmann et al, 1998) that was recently found to be formed in trace amounts in humans after intake of the soporific agent, chlo ral hydrate . The distinct toxic potency of TaClo (2) towards dopaminergic (Grote et al, 1995;Rausch et al, 1995) and sero tonergic (Gerlach et al, 1998; Bringmann et al, 2000a) neurons appears to be strongly associated with its ability to severely disturb the neuronal energy metabolism.…”