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

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 Previous investigations on rats and neuronal cell cultures repealed 2 to be capable of inducing severe disturbances on the dopamine metabolism.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.