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Structure modification of the cerebroprotective chroman amide 12 to improve the drug delivery to the target organ by protecting the active hydroxy functional 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 vivo antilipid peroxidation activity of 12P was significantly greater than the activity of 12 while the in vitro inhibition of 12P was found to be lower. These indicated that 12P with protected active group effectively reached the brain, the target site, but in vitro, 12P was unable to release its parent or released slowly. Neuropharmacological effect of 12P was investigated in mice. 12 and 12P (50-100 mg/kg, i.p.) showed significant suppression on the hypermotility induced by methamphetamine. 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 delivery and the antagonism against aberrant dopamine release. In the water maze test, 12P (200 mg/kg) as well as tacrine (3 mg/kg) significantly reduced the learning and memory impairment induced by scopolamine (0.5 mg/kg). The results support the enhanced brain delivery and the additional role of radical scavengers in the modulation of brain neurotransmitters in the aberrant condition.

Citation

O Vajragupta, O Monthakantirat, Y Wongkrajang, H Watanabe, P Peungvicha. Chroman amide 12P inhibition of lipid peroxidation and protection against learning and memory impairment. Life sciences. 2000 Aug 25;67(14):1725-34

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PMID: 11021357

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