NO-donor melatonin derivatives: synthesis and in vitro pharmacological characterization.
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.
Chegaev
Konstantin
K
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
Lazzarato
Loretta
L
Rolando
Barbara
B
Marini
Elisabetta
E
Tosco
Paolo
P
Cena
Clara
C
Fruttero
Roberta
R
Bertolini
Francesca
F
Reist
Marianne
M
Carrupt
Pierre-Alain
PA
Lucini
Valeria
V
Fraschini
Franco
F
Gasco
Alberto
A
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D000975:Antioxidants; D020030:Nitric Oxide Donors; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011994:Recombinant Proteins; D017392:Thiobarbituric Acid Reactive Substances; D000469:Alkaline Phosphatase; D008550:Melatonin