NO-Donor Melatonin Derivatives: Synthesis And In Vitro Pharmacological Characterization

Autor: Marianne Reist, Paolo Tosco, Clara Cena, Konstantin Chegaev, Valeria Lucini, Alberto Gasco, Franco Fraschini, Barbara Rolando, Pierre-Alain Carrupt, Elisabetta Marini, Loretta Lazzarato, Roberta Fruttero, Francesca Bertolini
Jazyk: angličtina
Rok vydání: 2007
Předmět:
Male
Antioxidant
medicine.medical_treatment
Receptor
Melatonin
MT1/metabolism
Nitric Oxide Donors/chemical synthesis/chemistry/pharmacology
melatonin
Thiobarbituric Acid Reactive Substances/metabolism
Protein oxidation
chemistry.chemical_compound
Endocrinology
Recombinant Proteins/metabolism
chemistry.chemical_classification
ddc:615
ABTS
Molecular Structure
Chemistry
Furoxan
Lipid Peroxidation/drug effects
Recombinant Proteins
Vasodilation
Melatonin/analogs & derivatives/chemical synthesis/pharmacology
antioxidants
Biochemistry
Microsomes
Liver/drug effects/metabolism
Microsomes
Liver
alkaline phosphatase
medicine.drug
In Vitro Techniques
multitarget drugs
nitric oxide-donors
thiobarbituric acid reactive substances assay
Thiobarbituric Acid Reactive Substances
Nitric oxide
Melatonin
medicine
TBARS
Animals
Humans
Nitric Oxide Donors
Rats
Wistar
Reactive oxygen species
Receptor
Melatonin
MT2
Receptor
Melatonin
MT1
Vasodilation/drug effects
Rats
Receptor
Melatonin
MT2/metabolism
Antioxidants/chemical synthesis/chemistry/pharmacology
Alkaline Phosphatase/metabolism
Lipid Peroxidation
Zdroj: Journal of Pineal Research, Vol. 42, No 4 (2007) pp. 371-85
ISSN: 0742-3098
Popis: Numerous studies document that melatonin possesses a broad-spectrum antioxidant activity. It traps a number of reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, singlet oxygen and hypochlorous acid. It also inhibits peroxynitrite-induced reactions. It is known that atherosclerosis progression involves ROS-induced oxidation of low-density lipoproteins in sub-endothelial space and the depletion of nitric oxide (NO) in blood vessels, as well as a decreased sensitivity of the vessels to the actions of NO. Considering this, a series of new NO-donor antioxidants were designed and synthesized by joining melatonin with NO-donor nitrooxy and furoxan moieties as polyvalent agents potentially useful for the treatment of cardiovascular diseases involving atherosclerotic vascular changes. The in vitro antioxidant properties of the resulting products were assessed in the thiobarbituric acid reactive substances assay (TBARS), the ABTS(+.) as well as in the alkaline phosphatase (ALP) assay. The antioxidant capacities of NO-donor melatonins to inhibit lipoperoxidation (TBARS-IC(50)) was predominantly dependent on their lipophilicity, and therefore on their partitioning process into membranes. On the other hand, their comparable capacity to inhibit protein oxidation (ALP-IC(50)) was independent of their lipophilicity and was consistent with their similar ability to participate in electron transfer reactions. All the NO-donor melatonins were also evaluated for their ability to relax rat aorta strips precontracted with 1 microM phenylephrine. Finally, binding affinities and intrinsic activity studies, carried out at MT(1) and MT(2) receptor subtypes, showed a rather complex picture in need of further investigation.
Databáze: OpenAIRE
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