BENZYLAMINE ANTIOXIDANTS - RELATIONSHIP BETWEEN STRUCTURE, PEROXYL RADICAL SCAVENGING, LIPID-PEROXIDATION INHIBITION, AND CYTOPROTECTION

Three homologous series of 3,5-dialkoxy-4-hydroxybenzylamines were pre pared and tested (1) as peroxyl radical scavengers in homogeneous aque ous solution, (2) as inhibitors of iron-dependent peroxidation of rabb it brain vesicular membrane lipids, and (3) as cytoprotective agents u sing primary cultures of rat hippocampal neurons exposed to hydrogen p eroxide. The structural requirements for efficient radical trapping in homogeneous solution differed from those for effective lipid peroxida tion inhibition: In homogeneous solution a kinetic preference existed for smaller, less sterically encumbered substituents flanking the reac tive phenolic hydroxyl group. Lipid peroxidation inhibition, on the ot her hand, required longer more lipophilic substituents. Consequently, a lipophilic alkoxyl substituent at C3 and a small substituent at C5 a ppeared optimal for efficient radical scavenging activity in both lipi d and homogeneous solution. Maximal cytoprotection of rat hippocampal neurons exposed to hydrogen peroxide was also associated with more lip ophilic derivatives although substituent length and substituent bulk m ay represent independent parameters for relating structure and efficac y in this system.