Natural tetrahydroisoquinoline

In vitro activity: Tetrahydropapaverine, one of the TIQs and an analogue of salsolinol and tetrahydropapaveroline, has been reported to have neurotoxic effects on dopamine neurons. Tetrahydropapaverine inhibits serotonin biosynthesis in serotonin-producing murine mastocytoma P815 cells with an IC50 of 7.5 μM and reduces tryptophan hydroxylase activity with an IC50 of 5.7 μM.

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The inhibitory effects of tetrahydropapaverine on serotonin biosynthesis in serotonin-producing murine mastocytoma P815 cells were investigated. Tetrahydropapaverine at concentration ranges of 5-20 microM decreased serotonin content in a concentration-dependent manner in P815 cells and showed 42.1% inhibition of serotonin content at 5.0 microM at 24 hr. The value of 50% inhibitory concentration, IC50, of tetrahydropapaverine was 6.2 microM. Under these conditions, tryptophan hydroxylase (EC 1.14.16.4, TPH) was inhibited for 24-36 hr after treatment with tetrahydropapaverine in P815 cells (49.1% inhibition at 7.5 microM). However, aromatic L-amino acid decarboxylase activity was not affected by tetrahydropapaverine. In addition, tetrahydropapaverine inhibited the activity of TPH, prepared from the P815 cells (P815-TPH), with the IC50 value of 5.7 microM. Tetrahydropapaverine un-competitively inhibited P815-TPH with the substrate L-tryptophan, and non-competitively with the cofactor DL-6-methyl-5,6,7,8-tetrahydropteridin. The Ki value of tetrahydropapaverine with L-tryptophan was 10.1 microM. These data indicate that tetrahydropapaverine leads to a decrease in serotonin content by the inhibition of TPH activity in P815 cells. [1] Researchers report neurotoxic effects of papaverine, tetrahydropapaverine, dimethoxyphenylethylamine (DMPEA), and 1-methyl-4-phenylpyridinium ion (MPP+) on dopaminergic neurons in ventral mesencephalic-striatal co-culture. These compounds have been reported as mitochondrial toxins which may be implicated in the etiology and pathogenesis of Parkinson's disease. Tyrosine hydroxylase (TH)-positive neurons were decreased in dose-dependent manner by these compounds. Papaverine and MPP+ were most toxic to TH-positive neurons among the compounds tested. The order of the toxicity on TH-positive neurons was papaverine, MPP+, tetrahydropapaverine and then DMPEA. This order of toxicity was approximately the same as that reported on the inhibitory effect of these compounds on NADH-linked mitochondrial respiration and complex I activity. These findings indicate that the presence of dimethoxy residues in the catechol ring augments toxicity to dopaminergic neurons in culture. [2]

Researchers report the toxic effects of 3,4-dimethoxyphenylethylamine (DMPEA), and tetrahydropapaverine (THP) on the rat nigrostriatal system; THP is a tetrahydroisoquinoline compound which may be derived from DMPEA by conjugation of DMPEA and its oxidative metabolite, dimethoxyphenylacetaldehyde; both are potent inhibitors of mitochondrial complex I. These compounds were introduced to the unilateral caudate-putamen of male Sprague-Dawley rats over 7 days using a 200-microl mini-osmotic pump. Striatal dopamine on the injected side showed a significant decrease to 86% of the non-injected side after 16.55 micromol/7 days infusion of DMPEA, and to 73% of the non-injected side after 7.90 micromol/7 days of THP infusion; as the non-injected side dopamine also reduced in the THP-injected rats, dopamine on the injected side was 55% of the saline control. Tyrosine hydroxylase (TH)-positive nigral neurons were decreased to 76% of the non-injected side after 16.55 micromol/7 days infusion of DMPEA and to 77% after 7.90 micromol/7 days of THP infusion. Dimethoxyphenyl-tetrahydroisoquinoline compounds appear to be potent nigral neurotoxins. [3]

The treatment of P815 cells with tetrahydropapaverine significantly reduced the intracellular serotonin content in a concentration-dependent manner. Tetrahydropapaverine decreased serotonin content by 57.9% at a concentration of 5.0 μM (Table 1). The IC50 value of tetrahydropapaverine was 6.2 μM (Table 1). Under these conditions, the intracellular TPH activity was significantly inhibited by the treatment with tetrahydropapaverine (49.1% inhibition at 7.5 μM) while AADC activity was not affected ... [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

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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)