Natural tetrahydroisoquinoline

体外活性：四氢罂粟碱是 TIQ 之一，也是 Salsolinol 和四氢罂粟碱的类似物，据报道对多巴胺神经元具有神经毒性作用。 Tetrahydropapaverine 抑制产生血清素的小鼠肥大细胞瘤 P815 细胞中的血清素生物合成，IC50 为 7.5 μM，并降低色氨酸羟化酶活性，IC50 为 5.7 μM。

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研究了四氢罂粟碱对产生血清素的小鼠肥大细胞瘤P815细胞血清素生物合成的抑制作用。四氢罂粟碱在5-20 μ m浓度范围内以浓度依赖的方式降低P815细胞血清素含量，在5.0 μ m浓度下，24小时血清素含量抑制率为42.1%。四氢罂粟碱50%抑制浓度（IC50）为6.2 μ m。在此条件下，四氢罂粟碱对P815细胞色氨酸羟化酶（EC 1.14.16.4， TPH）的抑制作用达到24-36小时（7.5 μ m时抑制49.1%）。而四氢罂粟碱对芳香族l -氨基酸脱羧酶活性没有影响。此外，四氢罂粟碱对P815细胞（P815-TPH）制备的TPH活性有抑制作用，IC50值为5.7 μ m。四氢罂粟碱与底物l-色氨酸无竞争性抑制P815-TPH，与辅因子dl -6-甲基-5,6,7,8-四氢罂粟碱无竞争性抑制P815-TPH。四氢罂粟碱与l -色氨酸的Ki值为10.1 μ m。这些数据表明，四氢罂粟碱通过抑制P815细胞的TPH活性导致血清素含量降低。［1］ 研究人员报道了罂粟碱、四氢罂粟碱、二甲氧基苯基乙胺（DMPEA）和1-甲基-4-苯基吡啶离子（MPP+）对腹侧中脑-纹状体共培养的多巴胺能神经元的神经毒性作用。这些化合物已被报道为线粒体毒素，可能与帕金森病的病因和发病机制有关。酪氨酸羟化酶（TH）阳性神经元呈剂量依赖性减少。罂粟碱和MPP+对th阳性神经元的毒性最大。对th阳性神经元的毒性程度依次为罂粟碱、MPP+、四氢罂粟碱、DMPEA。这种毒性顺序与报道的这些化合物对nadh相关的线粒体呼吸和复合体I活性的抑制作用大致相同。这些发现表明，儿茶酚环中二甲氧基残基的存在增加了培养中多巴胺能神经元的毒性。［２］

研究人员报告了3,4-二甲氧基苯乙胺（DMPEA）和四氢罂粟碱（THP）对大鼠黑纹状体系统的毒性作用；THP是一种四氢异喹啉化合物，可由DMPEA及其氧化代谢物二甲氧基苯乙醛偶联而得；这两种化合物都是线粒体复合物i的有效抑制剂。这些化合物通过200微利微渗透泵注入雄性Sprague-Dawley大鼠单侧尾壳核7天。注射侧纹状体多巴胺在注射DMPEA 16.55微mol/7 d后显著降低至非注射侧的86%，注射7.90微mol/7 d后显著降低至非注射侧的73%；由于注射thp的大鼠未注射侧多巴胺也减少，注射侧多巴胺为生理盐水对照组的55%。DMPEA注射16.55微mol/7 d后，酪氨酸羟化酶（TH）阳性的黑质神经元减少到未注射侧的76%，THP注射7.90微mol/7 d后减少到77%。二甲氧基苯基-四氢异喹啉化合物似乎是强效的神经毒素。 [3]

四氢罂粟碱处理P815细胞显著降低细胞内血清素含量呈浓度依赖性。在5.0 μM浓度下，四氢罂粟碱可使血清素含量降低57.9%（表1），IC50值为6.2 μM（表1）。在此条件下，四氢罂粟碱可显著抑制细胞内TPH活性（7.5 μM浓度下抑制49.1%），而AADC活性未受影响。［1］

[1]. Life Sci.2004 Sep 3;75(16):1949-57.
[2]. Brain Res.1997 Apr 18;754(1-2):260-8.
[3]. Brain Res. Brain Res. 1997 Oct 31;773(1-2):108-16.

Tetrahydroisoquinolines (TIQs) have been extensively studied to have a neurotoxic activity (Nagatsu, 1997) and an inhibitory effect on dopamine biosynthesis (Kim et al., 2001, Shih et al., 1999). TIQs are also structurally similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in human and non-human primates (McNaught et al., 1998). Among TIQs, salsolinol and tetrahydropapaveroline have been identified in the urine of Parkinsonian patients receiving L-DOPA therapy (Sandler et al., 1973) (Fig. 1). Salsolinol has been found to inhibit the activities of tyrosine hydroxylase (EC 1.14.16.2), the rate-limiting enzyme of catecholamine biosynthetic pathway (Minami et al., 1992) and TPH, the rate-limiting enzyme in serotonin biosynthesis (Ota et al., 1992). Tetrahydropapaveroline also inhibits the activity of tyrosine hydroxylase (Lee et al., 2001a).
Recently, it is reported that tetrahydropapaveroline inhibits dopamine biosynthesis by the inhibition of tyrosine hydroxylase in PC12 cells (Lee et al., 2001a) and also reduces serotonin content by the inhibition of TPH in murine mastocytoma P815 cells (Kim et al., 2003). In addition, tetrahydropapaveroline has been proven to non-competitively inhibit TPH activity with the substrate L-tryptophan (Kim et al., 2003).
Tetrahydropapaverine, one of the TIQs and an analogue of salsolinol and tetrahydropapaveroline, has been reported to have neurotoxic effects on dopamine neurons (Koshimura et al., 1997) (Fig. 1). However, the effects of tetrahydropapaverine on indoleamine biosynthesis or the metabolism of it have not been evaluated. The murine mastocytoma P815 cells are known to produce serotonin and to have a high TPH activity (Schindler et al., 1959). P815 cells also express histamine and L-histidine decarboxylase (Schindler et al., 1959, Imanishi et al., 1987).
The present study was, therefore, undertaken to investigate the inhibitory effects of tetrahydropapaverine on serotonin biosynthesis in P815 cells and TPH activity. The enzyme source of TPH was prepared from the P815 cells (P815-TPH).[1]

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces long-lasting parkinsonism in primates. The clinical features of MPTP-induced parkinsonism correlate with the loss of dopaminergic neurons and the depletion of dopamine in the nigro-striatal system. Hence, it has been speculated that Parkinson's disease may be induced by endogenous or environmental neurotoxins bioactivated in the brain, like MPTP, and this concept has opened up tremendous studies on potential nigral neurotoxins, both endogenous and exogenous. Among these compounds, tetrahydroisoquinolines (TIQs) and β-carbolines have been most extensively studied.
TIQs are contained in foods, such as cheese, wine, and cocoa, and can be easily transported to the brain, and some of the TIQ compounds have been found in both parkinsonian and normal human brains. Chronic administration of TIQ in monkeys produces Parkinson-like symptoms as well as significant decrease of dopamine and tyrosine hydroxylase (TH) activity in the substantia nigra. TIQ is metabolized to N-methyl-TIQ by N-methyl-transferase and the latter compound is oxidized to N-methyl-tetrahydroisoquinolinium ion by monoamine oxidase. This ion inhibits activities of TH and mitochondrial complex I, and neuronal growth in tissue culture.
β-Carbolines derived from indolamines have a structure closely related to MPP+ and some of the derivatives have been found in the human brain and shown to inhibit dopamine uptake, monoamine oxidase activity, mitochondrial respiration, and the growth of cultured PC12 cells.
While we were studying mitochondrial toxicity of these compounds, we found that compounds dimethoxylated in the catechol ring were more potent inhibitors of mitochondrial respiration. This observation prompted us to investigate toxicity of these compounds on cultured dopaminergic neurons.
For the purpose of the present study, we used dissociated mesencephalic-striatal co-cultures because they simulate more closely the in vivo condition containing trophic factors from target striatal neurons resulting in much better arborization of dendritic processes of dopaminergic neurons compared to the conventional mesencephalic cultures. The dimethoxy compounds tested in this study include tetrahydropapaverine, papaverine, their precursor dimethoxyphenylethylamine (DMPEA), and 1-methyl-4-phenylpyridinium ion (MPP+) as a positive control (Fig. 1).[2]

C20H25NO4.HCL

379.88

379.155

6429-04-5

(R)-Tetrahydropapaverine hydrochloride;54417-53-7

16667431

Typically exists as solid at room temperature

1.12g/cm3

475.8ºC at 760 mmHg

213-215ºC

202.7ºC

1.549

0.697

53.53

2

5

6

26

407

0

Cl[H].O(C([H])([H])[H])C1=C(C([H])=C2C([H])([H])C([H])([H])N([H])C([H])(C([H])([H])C3C([H])=C([H])C(=C(C=3[H])OC([H])([H])[H])OC([H])([H])[H])C2=C1[H])OC([H])([H])[H]

VMPLLPIDRGXFTQ-UHFFFAOYSA-N

InChI=1S/C20H25NO4.ClH/c1-22-17-6-5-13(10-18(17)23-2)9-16-15-12-20(25-4)19(24-3)11-14(15)7-8-21-16;/h5-6,10-12,16,21H,7-9H2,1-4H3;1H

1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;hydrochloride

6429-04-5; Tetrahydropapaverine hydrochloride; 1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride; Tetrahydropapaverine HCl; DL-Norlaudanosine hydrochloride; Norlaudanosine Hydrochloride; 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride; 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline;hydrochloride; Norlaudanosine HCl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.58 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.58 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.58 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。