1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related 
derivatives: Chemistry and biochemical effects on catecholamine biosynthesis

Bringmann, G.; Feineis, D.; God, R.; Peters, K.; Peters, E.-M.; Scholz, J.; Riederer, F.; Moser, A.

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1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: Chemistry and biochemical effects on catecholamine biosynthesis

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Peters, K.
Former Scientific Facilities, Max Planck Institute for Solid State Research, Max Planck Society;

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Peters, E.-M.
Former Scientific Facilities, Max Planck Institute for Solid State Research, Max Planck Society;

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Citation

Bringmann, G., Feineis, D., God, R., Peters, K., Peters, E.-M., Scholz, J., et al. (2002). 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) and related derivatives: Chemistry and biochemical effects on catecholamine biosynthesis. Bioorganic & Medicinal Chemistry, 10(7), 2207-2214.

Cite as: https://hdl.handle.net/21.11116/0000-000E-EDBF-1

Abstract

1-Trichloromethyl-1.2.3.4-tetrahydro-beta-carboline (TaClo, 2)
is a mammalian alkaloid that readily originates in the human
organism, by Pictet-Spengler condensation of endogenously
present tryptamine (Ta) and the non-natural hypnotic agent
trichloroacetaldehyde (chloral. Clo). Due to its structural
analogy to the neurotoxin 1-methyl-4-phenyl-1.2.3.6-
tetrahydropyridine (MPTP. 1). TaClo is discussed to possibly
contribute to the pathogenesis of Parkinson's disease acting as
an environmental toxin. Previous investigations on rats and
neuronal cell cultures repealed 2 to be capable of inducing
severe disturbances on the dopamine metabolism. In this paper,
c report on the effects of 2 on the activity of tyrosine
hydroxylase [L-tyrosine. tetrahydropteridine oxygen
oxidoreductase (3-hydroxylating). EC 1.14,6.2: TH] in vitro
using rat brain homogenates prepared from the TH-rich nucleus
accumbens. TaClo (2) dose-dependently inhibited basal TH
activity (IC50 = 3 muM), and after enzyme activation by
pituitary adenylate cyclase-activating polypeptide (PACAP-27),
it also reduced L-DOPA formation (IC50 = 15 muM). Moreover, two
presumable denylate TaClo metabolites, 2-methyl-TaClo (N-Me-
TaClo, 3) and 1-dichloromethylene-1,2.3.4-tetrahydro-beta-
carboline (1-CCl2-THbetaC. 4). which were synthesized in good
yields, also proved to be potent inhibitors of TH, with the
strongest effect on basal activity (similar to TaClo) being
obscerved for 3 (IC50 = 3 muM). In contrast to TaClo, however,
3 and 4 showed biphasic effects after TH activation with PACAP-
27, inducing a marked increase of enzyme activity in the
nanomolar range ( <0.1 μM), awhile TH activity was nearly
completely blocked at high concentrations (IC100 = 0.1 mM). An
X-ray diffraction investigation on the 3-dimensional structure
of the 1-CCl2-THβC-derived trifluoroacetamide 7 revealed
the voluminous and quite rigid dichloromethylene substituent to
be only moderately twisted out of the β-carboline ring
'plane'. thus resulting in an inreased ring strain of the
partially hydrogenated pyrido moiety accompanied by a strong
steric hindrance of Cl(1), Cl(2) C(13), and N(2), which pushes
the N-trifluoroacetyl group upwards to an even higher extent
than for the TaClo-related trifluoroacetamide 8. (C) 2002
Elsevier Science Ltd. All rights reserved.