Antioxidant properties of two novel 2-biphenylmorpholine compounds (EP2306 and EP2302) in vitro and in vivo.
The oxidation of low-density lipoprotein (LDL) is an important event in the development of atherosclerosis. In the present study, the antioxidant properties of two novel 2-biphenylmorpholine compounds (EP2306 and EP2302) were studied. Both compounds inhibited dose-dependently the in vitro oxidation of LDL induced by copper ions. EP2306 and EP2302 increased significantly the lag phase of the oxidation reaction at 0.1 and 10 microM, respectively, whereas they reduced the rate of the reaction at 1 and 10 microM, respectively. This inhibitory effect was not due to a free radical scavenging or copper-chelating activity of EP2300 compounds. Moreover, EP2306 and EP2302 inhibited 12-lipoxygenase activity dose-dependently with IC50 values of 454 and 318 microM, respectively, but had no effect on 15-lipoxygenase activity. In hyperlipidaemic rabbits treated with EP2306 for 4 weeks, there was a decrease in thiobarbituric acid-reactive substance (TBARS) levels and a significant increase in total peroxyl radical-trapping potential (TRAP) levels as compared to control animals. The present data suggest that EP2300 compounds are effective inhibitors of copper-mediated LDL oxidation in vitro. Moreover, EP2306 acts as an antioxidant in hyperlipidaemic rabbits, a property which could be beneficial in reducing atherosclerosis.
Tavridou
Anna
A
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, I. Kavyri 6, 68100 Alexandroupolis, Greece.
Manolopoulos
Vangelis G
VG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003300:Copper / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism / Q000517:prevention & control; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D011817:Rabbits; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D001713:Biphenyl Compounds; C500325:EP2302; C500324:EP2306; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D009025:Morpholines; D017392:Thiobarbituric Acid Reactive Substances; D003300:Copper; D008084:Lipoxygenase