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L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties.
J Med Chem 2006; 49(4):1486-93JM

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.

Authors+Show Affiliations

Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy. adistefano@unich.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16480285

Citation

Di Stefano, Antonio, et al. "L-dopa- and dopamine-(R)-alpha-lipoic Acid Conjugates as Multifunctional Codrugs With Antioxidant Properties." Journal of Medicinal Chemistry, vol. 49, no. 4, 2006, pp. 1486-93.
Di Stefano A, Sozio P, Cocco A, et al. L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. J Med Chem. 2006;49(4):1486-93.
Di Stefano, A., Sozio, P., Cocco, A., Iannitelli, A., Santucci, E., Costa, M., ... Pinnen, F. (2006). L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. Journal of Medicinal Chemistry, 49(4), pp. 1486-93.
Di Stefano A, et al. L-dopa- and dopamine-(R)-alpha-lipoic Acid Conjugates as Multifunctional Codrugs With Antioxidant Properties. J Med Chem. 2006 Feb 23;49(4):1486-93. PubMed PMID: 16480285.
* Article titles in AMA citation format should be in sentence-case
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 DB - PRIME DP - Unbound Medicine ER -