Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,2,3,4-Tetrahydroisoquinoline (TIQ), which is structurally similar to MPTP, has been found in human brain and has been reported to inhibit the mitochondrial respiration as does 1-methyl-4-phenylpyridinium ion (MPP+). However, the potency of inhibition by TIQ is less than that of MPP+. In this study, we report the effects of N-methyl-1,2,3,4-tetrahydroisoquinoline (N-Me-TIQ) and N-methylisoquinolinium ion (N-Me-IQ+) on the mitochondrial electron transport system using mitochondria prepared from mouse brains. Five mM N-Me-TIQ and 500 microM N-Me-IQ+ inhibited complex I activity to 54% and 63% of the control, respectively. The IC50 of N-Me-TIQ and N-Me-IQ+ were approximately 6.5 mM and 650 microM, respectively. Neither substance inhibited complex II, III and IV activities. Kinetic analyses of N-Me-IQ+ on complex I activity revealed uncompetitive inhibition against NADH and non-competitive inhibition against ubiquinone. These inhibitory characteristics were the same to those of MPP+ and the inhibitory potency of N-Me-IQ+ on complex I activity was stronger than that of MPP+.
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PMID:Selective inhibition of complex I by N-methylisoquinolinium ion and N-methyl-1,2,3,4-tetrahydroisoquinoline in isolated mitochondria prepared from mouse brain. 135 9

Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 approximately 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP+, so respiratory inhibition may underlie their reported neurotoxicity.
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PMID:Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 861 71

Malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, is frequently used as a model neurotoxin to produce lesion of the nigrostriatal dopaminergic system in animals due to particular sensitivity of dopamine neurons to mild energy impairment. This model of neurotoxicity was applied in our study to explore neuroprotective potential of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance whose function in the mammalian brain, despite extensive studies, has not been elucidated so far. Injection of malonate at a dose of 3 mumol unilaterally into the rat left medial forebrain bundle resulted in the 54% decrease in dopamine (DA) concentration in the ipsilateral striatum and, depending on the examined striatum regions, caused 24-44% reduction in [3H]GBR12,935 binding to the dopamine transporter (DAT). TIQ (50 mg/kg i.p.) administered 4 h before malonate infusion and next once daily for successive 7 days prevented both these effects of malonate. Such TIQ treatment restored DA content and DAT binding almost to the control level. The results of the present study indicate that TIQ may act as a neuroprotective agent in the rat brain. An inhibition of the enzymatic activities of monoamine oxidase and gamma-glutamyl transpeptidase as well as an increase in the striatal levels of glutathione and nitric oxide found after TIQ administration and reported in our earlier studies are considered to be potential factors that may be involved in the TIQ-mediated protection of dopamine terminals from malonate toxicity.
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PMID:1,2,3,4-Tetrahydroisoquinoline protects terminals of dopaminergic neurons in the striatum against the malonate-induced neurotoxicity. 1600 76