Chroman amide 12P Inhibition of lipid peroxidation and protection against learning and memory impairment

Structure modification of the cerebroprotective chroman amide 12 to improve the drug delivery to the target organ by protecting the active hydroxy fun ctional group was carried out in this study. Chroman amide 12P, which the O -acetyl group was served to protect the active group to be delivered to the target organ, was synthesized. Ex vitro antilipid peroxidation activity of 12P was significantly greater than the activity of 12 while the bt vitro i nhibition of 12P was found to be lower, These indicated that 12P with prote cted active group effectively reached the brain, the target site, but in vi tro, 12P was unable to release its parent or released slowly. Neuropharmaco logical effect of 12P was investigated in mice. 12 and 12P (50-100 mg/kg, i .p.) showed significant suppression on the hypermotility induced by methamp hetamine. 12P (100 mg/kg, i.p.) was more potent than 12, 54.36% and 38.73% suppression, respectively. The result suggested the enhancement of brain de livery and the antagonism against aberrant dopamine release. In the water m aze lest, 12P (200 mg/kg) as well as tacrine (3 mg/kg) significantly reduce d the learning and memory impairment induced by scopolamine (0.5 mg/kg). Th e results support the enhanced brain delivery and the additional role of ra dical scavengers in the modulation of brain neurotransmitters in the aberra nt condition. (C) 2000 Elsevier Science Inc. All rights reserved.