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-β-carboline (TaClo) and related derivatives:: Chemistry and biochemical effects on catecholamine biosynthesis
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DOI：
10.1016/s0968-0896(02)00060-3
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发表时间：
2002-07-01
影响因子：
3.5
通讯作者：
Moser, A
中科院分区：
文献类型：
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作者：
Bringmann, G;Feineis, D;Moser, A
1-Trichloromethyl-1.2.3.4-tetrahydro-beta-carboline(Taclo，2)是一种哺乳动物生物碱，由内源性色胺(Ta)和非天然催眠剂三氯乙醛(Cloual)经Pictet-Spengler缩合而成，很容易在人体内产生。CLO)。由于其结构类似于神经毒素1-甲基-4-苯基-1.2.3.6-四氢吡啶(MPTP.1)。Taclo被认为可能与帕金森氏病的发病机制有关，它是一种环境毒素。以前对大鼠和神经细胞培养的研究废除了2，因为它能够引起对多巴胺代谢的严重干扰。本文报道了2对酪氨酸羟化酶[L-酪氨酸]活性的影响。四氢蝶啶氧还原酶(3-羟基化)。EC 1.14，6.2：TH]使用从富含TH的伏隔核制备的大鼠脑匀浆进行体外实验。Taclo(2)呈剂量依赖性地抑制基础TH活性(IC_(50)=3um)，经垂体腺苷环化酶激活多肽(PACAP-27)激活后，也可抑制L-DOPA的形成(IC_(50)=15um)。2-甲基-Taclo(N-Me-Taclo，3)和1-dichloromethylene-1，2.3.4-tetrahydro-beta-carboline(1-CCl_2-THbetaC.4)。它们也被证明是TH的有效抑制剂，对基础活性(与Taclo相似)的影响最大的是3(IC_(50)=3um)。然而，与Taclo相反，PACAP-27激活TH后，3和4表现出双相效应，导致纳摩尔范围内的酶活性显著增加(
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 Previous investigations on rats and neuronal cell cultures repealed 2 to be capable of inducing severe disturbances on the dopamine metabolism.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 (