Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson’s disease

Abe, Kenji; Taguchi, Kyoji; Wasai, Tomoko; Ren, Jin; Utsunomiya, Iku; Shinohara, Takayuki; Miyatake, Tadashi; Sano, Takehiro

doi:10.1016/s0361-9230(01)00603-7

Cited by 36 publications

(35 citation statements)

References 32 publications

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“…Many chiral TIQ molecules have been shown to exhibit enantioselective neurotoxicity. 14,15 (S)-Sal was shown to significantly suppress pro-opiomelanocotin (POMC) gene expression, but the (R)-enantiomer did not exhibit the same effect. 16 After being administered into the striatum, the (R)-enantiomer of N-methyl-Sal induced Parkinsonism in rats, while the (S)-enantiomer did not.…”

Section: Introductionmentioning

confidence: 99%

Chiral CE Separation of Dopamine-Derived Neurotoxins

et al. 2005

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An enantiomeric separation of dopamine-derived neurotoxins by capillary electrophoresis has been developed. Tetrahydroisoquinoline (TIQ), dopamine (DA), (R/S)-1-benzyl-TIQ (BTIQ), (R/S)-6,7-dihydroxy-1-methyl-TIQ (salsolinol, Sal), and (R/S)-6,7-dihydroxy-1, 2-dimethyl-TIQ (N-methyl-salsolinol, NMSal) were studied as model compounds. The CE running buffer (50 mM phosphate buffer at pH 3.0) contained 1.5 M urea and 12 mM β-CD as a chiral selector. During separation, the (R)-enantiomers formed more stable inclusion complexes with β-CD, and thus had a longer migration time than their optical antipodes. It was noticed that the recovery rates of these TIQ derivatives were very poor (< 15%) during protein precipitation, a procedure widely used for cleaning up biological samples. The recovery was significantly improved by pre-mixing the sample with a surfactant (e.g., sodium hexanesulfonate or Triton X-100) to reduce the co-precipitation. The present method in combination with electrospray ionization tandem mass spectrometry (ESI-MS/MS) was applied to study samples obtained from in vitro incubation of two catecholamines, dopamine and epinine, with aldehydes forming neurotoxins including (S)-and (R)-NMSal enantiomers. The later is known to induce Parkinsonism in rats.

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Section: Introductionmentioning

confidence: 99%

Chiral CE Separation of Dopamine-Derived Neurotoxins

et al. 2005

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“…Our previous study also showed that repeated treatment with TIQ decreased the DA content of the striatum and induced a loss of TH-positive cells in the substantia nigra of mice. 71) These biochemical studies indicated that TIQ damaged the nigrostriatal pathway and either facilitated or inhibited DA release in vivo. In addition, our data showed that doses producing behavioral abnormality did not reduce ligand and DA transporter (DAT) binding in the striatum of TIQ treated mice.…”

Section: Neurotoxicity Of 1234-tetrahydroiso-quinoline (Tiq)mentioning

confidence: 97%

“…71) We also investigated the stereoisomer effects of 1-methyl-TIQ on TIQ-induced parkinsonism using (R)-and (S)-enantiomers. Our results showed that (R)-1-methyl-TIQ was a potent inhibitor of TIQinduced bradykinesia.…”

Section: Neuroprotection Of 1-methyl-1234-tetrahydroisoquinoline (mentioning

confidence: 99%

“…Moreover, (R)-1-methyl-TIQ prevented the loss of TH-positive cells in the substantia nigra pars compacta and decreased DA in the striatum compared to (S)-1-methyl-TIQ. 71) Recently, (R)-1-methyl-TIQ was found to exert a dose-dependent neuroprotective effect on physiological neuronal cell death, while (S)-1-methyl-TIQ had little effect. 83) From these results, we initially thought that (R)-1-methyl-TIQ played a crucial role in TIQ-induced PD-like symptoms.…”

Section: Neuroprotection Of 1-methyl-1234-tetrahydroisoquinoline (mentioning

confidence: 99%

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Synthesis and Neurotoxicity of Tetrahydroisoquinoline Derivatives for Studying Parkinson's Disease

Abe

Saitoh

Horiguchi

et al. 2005

Biological & Pharmaceutical Bulletin

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Parkinson's disease involves the progressive degeneration of dopaminergic neurons in the substantia nigra. However, the etiology of the disease remains to be elucidated. Endogenous amines, such as 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives present in the mammalian brain, are known to participate in the pathogenesis of Parkinson's disease. These endogenous neurotoxins have been extensively studied because of their structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an agent widely used for generating animal models of Parkinson's disease-like symptoms. Investigations of the synthesis and pharmacological properties of TIQ derivatives are expected to contribute to the development of new therapeutic agents for treating Parkinson's disease. In the present study, we describe more efficient synthesis methods for TIQ derivatives via Pummerertype cyclization of the substrate N-acyl sulfoxide. Furthermore, the modified Pummerer reaction provided a convenient and efficient method for synthesizing various TIQs. TIQ and its derivative, 1-benzyl-TIQ, can induce parkinsonism in primates and rodents. On the other hand, one TIQ derivative, 1-methyl-TIQ, has been shown to prevent MPTP, TIQ, and 1-benzyl-TIQ induced behavioral abnormalities. Therefore, TIQ derivatives are considered to play an important role in both the onset and prevention of Parkinson's disease. In this article, we focus on the synthesis and pharmacological aspects of 1,2,3,4-tetrahydroisoquinoline derivatives in Parkinson's disease.

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“…rotenone. 9,22,23) We have reported parkinsonism-preventing substance having a TIQ moiety was only 1MeTIQ, but that three novel compounds were found in its derivatives. The present report is the first to show that 1MeTIQ and its derivatives reverse the decrease of dopamine induced by MPTP.…”

Section: )mentioning

confidence: 99%

Parkinsonism-Preventing Activity of 1-Methyl-1,2,3,4-tetrahydroisoquinoline Derivatives in C57BL Mouse in Vivo

Okuda

Kotake

Ohta

2006

Biological & Pharmaceutical Bulletin

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Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration of nigro-striatal dopaminergic neurons and reduction in the level of dopamine in this area. Since the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could induce parkinsonism in humans, 1) 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been considered as candidate endogenous causative factors of idiopathic Parkinson's disease (PD), because of their structural similarity to MPTP. We have reported that tetrahydroisoquinoline derivatives (Fig. 1), such as TIQ, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ),2) 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), 3) and 1-(3Ј,4Ј-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3Ј,4ЈDHBnTIQ), 4) exist in the brain of mammalians of several species. While the content of 1BnTIQ tends to be increased in cerebrospinal fluid (CSF) of PD patients, 3) 1MeTIQ is significantly decreased in the parkinsonian brain and MPTP-injected mouse brain. 5,6) Bradykinesia, one of the symptoms of PD, was induced by injection of TIQ, 1BnTIQ, or 3Ј,4ЈDHBnTIQ in mice, 2,3) so these TIQ derivatives are considered to be parkinsonism-inducing substances. MPTP and TIQ derivatives have inhibitory activities towards complex I of the mitochondrial respiratory chain and tyrosine hydroxylase. 9) Thus, 1MeTIQ is a possible endogenous PD-preventing substance. Since 1MeTIQ is an endogenous amine, it may be synthesized enzymatically. Indeed, a candidate enzyme was partially purified from mitochondrial-synaptosomal fraction of rat brain, 10) and its regional distribution was examined in monkey brain.11) However, the mechanism of the parkinsonism-preventing activity of 1MeTIQ is still unknown.We have synthesized derivatives of 1MeTIQ ( Fig. 1) and evaluated their in vitro neurotoxicity and protective activity against toxicity due to salsolinol in SH-SY5Y human neuroblastoma cells.12) The introduction of one methoxyl group into 1MeTIQ increased the toxicity, especially in the case of 7-methoxy-1MeTIQ. The introduction of one hydroxyl group, however, reduced the toxicity. 1MeTIQ showed a week (not statistically significant) in vitro protective effect against the toxicity of salsolinol. 6-or 7-Hydroxy-1MeTIQ showed a greater (statistically significant) protective effect at 20 mM concentration against the toxicity of 20 or 40 mM salsolinol.In the present study, we examined whether these hydroxylsubstituted 1MeTIQ derivatives have parkinsonism-preventing activity in C57BL/6N mice by means of the pole test, and measured the brain dopamine content. MATERIALS AND METHODSReagents 1MeTIQ, 5-hydroxy-1MeTIQ, 6-hydroxy1MeTIQ and 7-hydroxy-1MeTIQ were synthesized according to the literature. 6,12,13) Treatment of the Reagents Twenty-four C57BL/6N male mice were divided into six groups (nϭ4) with the aid of a table of random numbers. Saline or a 1MeTIQ derivative Minami-ku, Hiroshima 734-8553, Japan. Received February 28, 2006; accepted April 17, 2006; published online April 21, 2006 1- Methyl-1,2,3,4-tetrah...

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Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson’s disease

Cited by 36 publications

References 32 publications

Chiral CE Separation of Dopamine-Derived Neurotoxins

Chiral CE Separation of Dopamine-Derived Neurotoxins

Synthesis and Neurotoxicity of Tetrahydroisoquinoline Derivatives for Studying Parkinson's Disease

Parkinsonism-Preventing Activity of 1-Methyl-1,2,3,4-tetrahydroisoquinoline Derivatives in C57BL Mouse in Vivo

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