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L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties.

Abstract

A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs 1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA. This evidence, together with the "in vivo" dopaminergic activity and a sustained release of the parent drug in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in treating pathologies such as Parkinson's disease, characterized by an evident decrease of DA concentration in the brain.

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  • Authors+Show Affiliations

    ,

    Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy. adistefano@unich.it

    , , , , , , , ,

    Source

    Journal of medicinal chemistry 49:4 2006 Feb 23 pg 1486-93

    MeSH

    Animals
    Antioxidants
    Biomarkers
    Dopamine
    Dopamine Agonists
    Drug Stability
    Free Radical Scavengers
    Glutathione Peroxidase
    Humans
    Hydrogen-Ion Concentration
    Hydrolysis
    In Vitro Techniques
    Iron Chelating Agents
    Kinetics
    Levodopa
    Male
    Motor Activity
    Oxidative Stress
    Rats
    Rats, Wistar
    Solubility
    Stereoisomerism
    Structure-Activity Relationship
    Superoxide Dismutase
    Thioctic Acid

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16480285

    Citation

    TY - JOUR T1 - L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. AU - Di Stefano,Antonio, AU - Sozio,Piera, AU - Cocco,Alessandra, AU - Iannitelli,Antonio, AU - Santucci,Eleonora, AU - Costa,Mara, AU - Pecci,Laura, AU - Nasuti,Cinzia, AU - Cantalamessa,Franco, AU - Pinnen,Francesco, PY - 2006/2/17/pubmed PY - 2006/4/11/medline PY - 2006/2/17/entrez SP - 1486 EP - 93 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 49 IS - 4 N2 - A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs 1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA. This evidence, together with the "in vivo" dopaminergic activity and a sustained release of the parent drug in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in treating pathologies such as Parkinson's disease, characterized by an evident decrease of DA concentration in the brain. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/16480285/full_citation L2 - https://dx.doi.org/10.1021/jm051145p ER -