L-Dopa− and Dopamine−(R)-α-Lipoic Acid Conjugates as Multifunctional Codrugs with Antioxidant Properties

• Published in: Journal of medicinal chemistry Vol. 49; no. 4; pp. 1486 - 1493
• Main Authors: Di Stefano, Antonio, Sozio, Piera, Cocco, Alessandra, Iannitelli, Antonio, Santucci, Eleonora, Costa, Mara, Pecci, Laura, Nasuti, Cinzia, Cantalamessa, Franco, Pinnen, Francesco
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.02.2006; Amer Chemical Soc
• Subjects: Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Biological and medical sciences; Biomarkers - blood; Chemistry, Medicinal; Dopamine - chemistry; Dopamine Agonists - chemical synthesis; Dopamine Agonists - chemistry; Dopamine Agonists - pharmacology; Drug Stability; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Glutathione Peroxidase - blood; Humans; Hydrogen-Ion Concentration; Hydrolysis; In Vitro Techniques; Iron Chelating Agents - chemistry; Kinetics; Levodopa - chemistry; Levodopa - pharmacology; Life Sciences & Biomedicine; Male; Medical sciences; Motor Activity - drug effects; Neuropharmacology; Oxidative Stress; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Wistar; Science & Technology; Solubility; Stereoisomerism; Structure-Activity Relationship; Superoxide Dismutase - blood; Thioctic Acid - chemistry; HYDROXYL RADICALS; IN-VITRO; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE ACTIVITY; L-DOPA; GLUTATHIONE-PEROXIDASE; ALPHA-LIPOIC ACID; PC12 CELLS; ASCORBIC-ACID; PARKINSONS-DISEASE; Dopamine; Thioctic acid; Rat; Rodentia; Solubility; Partition coefficient; Antioxidant; Catecholamine; Antiparkinson agent; Biological activity; Non steroidal antiinflammatory agent; Locomotion; Hydrolysis resistance; Vertebrata; Mammalia; Animal; Neurotransmitter; Arylpropionic acid derivatives; Levodopa; Conjugated compound; Chemical synthesis; Lipophilicity; Physicochemical properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051145p

A series of multifunctional codrugs (1−4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-α-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.