Isoquinoline

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C. D. Marsden - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of [3H]dopamine uptake into striatal synaptosomes by Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    Biochemical Pharmacology, 1996
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary Isoquinoline derivatives (7 Isoquinolines, 2 dihydroIsoquinolines and 5 1,2,3,4-tetrahydroIsoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten Isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 Isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that Isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, Isoquinoline derivatives may be necessary to cause neurodegeneration.

  • Effects of Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration
    Biochemical Pharmacology, 1996
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Abstract Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP + )-like activity as inhibitors of complex I and α-ketoglutarate dehydrogenase activity in rat brain mitochondrial fragments. We now examine the ability of 19 Isoquinoline derivatives and MPP + to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited respiration supported by either succinate + rotenone or tetramethylparaphenylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 Isoquinoline derivatives and MPP + inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manner. None of the Isoquinoline derivatives were more potent than MPP + . 6,7-Dimethoxy-1-styryl-3,4-dihydroIsoquinoline uncoupled mitochondrial respiration. Qualitative structure-activity relationship studies revealed that isoquinolinium cations were more active than Isoquinolines in inhibiting mitochondrial respiration; these, in turn, were more active than dihydroIsoquinolines and 1,2,3,4-tetrahydroIsoquinolines. Three-dimensional quantitative structure-activity relationship studies using Comparative Molecular Field Analysis showed that the inhibitory potency of Isoquinoline derivatives was determined by steric, rather than electrostatic, properties of the compounds. A hypothetical binding site was identified that may be related to a rate-limiting transport process, rather than to enzyme inhibition. In conclusion, Isoquinoline derivatives are less potent in inhibiting respiration in intact mitochondria than impairing complex I activity in mitochondrial fragments. This suggests that Isoquinoline derivatives are not accumulated by mitochondria as avidly as MPP + . The activity of charged and neutral Isoquinoline derivatives implicates both active and passive processes by which these compounds enter mitochondria, although the quaternary nitrogen moiety of the isoquinolinium cations favours mitochondrial accumulation and inhibition of respiration. These findings suggest that Isoquinoline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP + .

  • Inhibition of complex I by Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)
    Biochemical Pharmacology, 1995
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurode-generative 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 ≈ 22 mM). At 10 mM, only Isoquinoline (23.1%), 6,7-dimethoxyIsoquinoline (89.6%), and N-ethylsalsolinol (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.

Shubhankar Samanta - One of the best experts on this subject based on the ideXlab platform.

  • An efficient synthesis of pyrrole and fluorescent Isoquinoline derivatives using NaN3/NH4Cl promoted intramolecular aza-annulation
    Tetrahedron Letters, 2016
    Co-Authors: Akash Jana, Susanta Kumar Manna, Suresh Kumar Mondal, Arabinda Mandal, Saikat Kumar Manna, Avijit Jana, Bidyut Kumar Senapati, Manas Jana, Shubhankar Samanta
    Abstract:

    Abstract An efficient synthetic protocol of pyrroles and Isoquinolines through NaN3/NH4Cl promoted intramolecular aza-annulation of formyl group with suitable alkenes or alkynes is described in high yield and regioselectivities. The metal free exo-trig and endo-dig aza-cyclisation has been extended for the synthesis of bicyclic or tricyclic pyrroles along with environment sensitive fluorescent Isoquinoline derivatives. Reactions occur in excellent yields, broad scope and high tolerance of functional groups. The synthetic utility of this methodology was demonstrated in the short synthesis of the core structure of lamellarin Q.

  • an efficient synthesis of pyrrole and fluorescent Isoquinoline derivatives using nan3 nh4cl promoted intramolecular aza annulation
    Tetrahedron Letters, 2016
    Co-Authors: Akash Jana, Susanta Kumar Manna, Suresh Kumar Mondal, Arabinda Mandal, Saikat Kumar Manna, Avijit Jana, Bidyut Kumar Senapati, Manas Jana, Shubhankar Samanta
    Abstract:

    Abstract An efficient synthetic protocol of pyrroles and Isoquinolines through NaN3/NH4Cl promoted intramolecular aza-annulation of formyl group with suitable alkenes or alkynes is described in high yield and regioselectivities. The metal free exo-trig and endo-dig aza-cyclisation has been extended for the synthesis of bicyclic or tricyclic pyrroles along with environment sensitive fluorescent Isoquinoline derivatives. Reactions occur in excellent yields, broad scope and high tolerance of functional groups. The synthetic utility of this methodology was demonstrated in the short synthesis of the core structure of lamellarin Q.

Kevin St. P. Mcnaught - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of [3H]dopamine uptake into striatal synaptosomes by Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    Biochemical Pharmacology, 1996
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary Isoquinoline derivatives (7 Isoquinolines, 2 dihydroIsoquinolines and 5 1,2,3,4-tetrahydroIsoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten Isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 Isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that Isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, Isoquinoline derivatives may be necessary to cause neurodegeneration.

  • Effects of Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration
    Biochemical Pharmacology, 1996
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Abstract Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP + )-like activity as inhibitors of complex I and α-ketoglutarate dehydrogenase activity in rat brain mitochondrial fragments. We now examine the ability of 19 Isoquinoline derivatives and MPP + to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited respiration supported by either succinate + rotenone or tetramethylparaphenylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 Isoquinoline derivatives and MPP + inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manner. None of the Isoquinoline derivatives were more potent than MPP + . 6,7-Dimethoxy-1-styryl-3,4-dihydroIsoquinoline uncoupled mitochondrial respiration. Qualitative structure-activity relationship studies revealed that isoquinolinium cations were more active than Isoquinolines in inhibiting mitochondrial respiration; these, in turn, were more active than dihydroIsoquinolines and 1,2,3,4-tetrahydroIsoquinolines. Three-dimensional quantitative structure-activity relationship studies using Comparative Molecular Field Analysis showed that the inhibitory potency of Isoquinoline derivatives was determined by steric, rather than electrostatic, properties of the compounds. A hypothetical binding site was identified that may be related to a rate-limiting transport process, rather than to enzyme inhibition. In conclusion, Isoquinoline derivatives are less potent in inhibiting respiration in intact mitochondria than impairing complex I activity in mitochondrial fragments. This suggests that Isoquinoline derivatives are not accumulated by mitochondria as avidly as MPP + . The activity of charged and neutral Isoquinoline derivatives implicates both active and passive processes by which these compounds enter mitochondria, although the quaternary nitrogen moiety of the isoquinolinium cations favours mitochondrial accumulation and inhibition of respiration. These findings suggest that Isoquinoline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP + .

  • Inhibition of complex I by Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)
    Biochemical Pharmacology, 1995
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurode-generative 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 ≈ 22 mM). At 10 mM, only Isoquinoline (23.1%), 6,7-dimethoxyIsoquinoline (89.6%), and N-ethylsalsolinol (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.

Akash Jana - One of the best experts on this subject based on the ideXlab platform.

  • An efficient synthesis of pyrrole and fluorescent Isoquinoline derivatives using NaN3/NH4Cl promoted intramolecular aza-annulation
    Tetrahedron Letters, 2016
    Co-Authors: Akash Jana, Susanta Kumar Manna, Suresh Kumar Mondal, Arabinda Mandal, Saikat Kumar Manna, Avijit Jana, Bidyut Kumar Senapati, Manas Jana, Shubhankar Samanta
    Abstract:

    Abstract An efficient synthetic protocol of pyrroles and Isoquinolines through NaN3/NH4Cl promoted intramolecular aza-annulation of formyl group with suitable alkenes or alkynes is described in high yield and regioselectivities. The metal free exo-trig and endo-dig aza-cyclisation has been extended for the synthesis of bicyclic or tricyclic pyrroles along with environment sensitive fluorescent Isoquinoline derivatives. Reactions occur in excellent yields, broad scope and high tolerance of functional groups. The synthetic utility of this methodology was demonstrated in the short synthesis of the core structure of lamellarin Q.

  • an efficient synthesis of pyrrole and fluorescent Isoquinoline derivatives using nan3 nh4cl promoted intramolecular aza annulation
    Tetrahedron Letters, 2016
    Co-Authors: Akash Jana, Susanta Kumar Manna, Suresh Kumar Mondal, Arabinda Mandal, Saikat Kumar Manna, Avijit Jana, Bidyut Kumar Senapati, Manas Jana, Shubhankar Samanta
    Abstract:

    Abstract An efficient synthetic protocol of pyrroles and Isoquinolines through NaN3/NH4Cl promoted intramolecular aza-annulation of formyl group with suitable alkenes or alkynes is described in high yield and regioselectivities. The metal free exo-trig and endo-dig aza-cyclisation has been extended for the synthesis of bicyclic or tricyclic pyrroles along with environment sensitive fluorescent Isoquinoline derivatives. Reactions occur in excellent yields, broad scope and high tolerance of functional groups. The synthetic utility of this methodology was demonstrated in the short synthesis of the core structure of lamellarin Q.

Ulrike Thull - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of [3H]dopamine uptake into striatal synaptosomes by Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    Biochemical Pharmacology, 1996
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary Isoquinoline derivatives (7 Isoquinolines, 2 dihydroIsoquinolines and 5 1,2,3,4-tetrahydroIsoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten Isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 Isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that Isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, Isoquinoline derivatives may be necessary to cause neurodegeneration.

  • Effects of Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration
    Biochemical Pharmacology, 1996
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Abstract Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP + )-like activity as inhibitors of complex I and α-ketoglutarate dehydrogenase activity in rat brain mitochondrial fragments. We now examine the ability of 19 Isoquinoline derivatives and MPP + to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited respiration supported by either succinate + rotenone or tetramethylparaphenylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 Isoquinoline derivatives and MPP + inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manner. None of the Isoquinoline derivatives were more potent than MPP + . 6,7-Dimethoxy-1-styryl-3,4-dihydroIsoquinoline uncoupled mitochondrial respiration. Qualitative structure-activity relationship studies revealed that isoquinolinium cations were more active than Isoquinolines in inhibiting mitochondrial respiration; these, in turn, were more active than dihydroIsoquinolines and 1,2,3,4-tetrahydroIsoquinolines. Three-dimensional quantitative structure-activity relationship studies using Comparative Molecular Field Analysis showed that the inhibitory potency of Isoquinoline derivatives was determined by steric, rather than electrostatic, properties of the compounds. A hypothetical binding site was identified that may be related to a rate-limiting transport process, rather than to enzyme inhibition. In conclusion, Isoquinoline derivatives are less potent in inhibiting respiration in intact mitochondria than impairing complex I activity in mitochondrial fragments. This suggests that Isoquinoline derivatives are not accumulated by mitochondria as avidly as MPP + . The activity of charged and neutral Isoquinoline derivatives implicates both active and passive processes by which these compounds enter mitochondria, although the quaternary nitrogen moiety of the isoquinolinium cations favours mitochondrial accumulation and inhibition of respiration. These findings suggest that Isoquinoline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP + .

  • Inhibition of complex I by Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)
    Biochemical Pharmacology, 1995
    Co-Authors: Kevin St. P. Mcnaught, Ulrike Thull, Pierre-alain Carrupt, Cosimo Altomare, Saverio Cellamare, Angelo Carotti, Bernard Testa, Peter Jenner, C. D. Marsden
    Abstract:

    Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurode-generative 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 ≈ 22 mM). At 10 mM, only Isoquinoline (23.1%), 6,7-dimethoxyIsoquinoline (89.6%), and N-ethylsalsolinol (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.