Hypnotic and antinociceptive effects of N3-substituted oxopyrimidines and their mechanism

点击翻译按钮获取中文摘要

N^3-Substituted oxopyrimidine nucleosides are known to possess central nervous system depressant effects such as hypnotic activity and antinociceptive effect. We synthesized N^3-substituted oxopyrimidine nucleosides such as benzyl, phenacyl and their related group substituted analogues. N^3-Nitrobenzyl and N^3-(2'-cyanobenzyl)-arabinofuranosyluracil possessed strong hypnotic activity at 2.0 umol/mouse by i.c.v. injection. N^3-(2',5'-Dimethoxyphenacyl)-arabinofuranosyluracil (N^3-(2',5'-DiMeOPhAc)-AraU) was found to exhibit the antinociceptive effects without the hypnotic activity in mice, and the effects was inhibited by naloxone. We report interaction of N^3-(2',5'-DiMeOPhAc)-AraU with opioid receptors using rat brain slice. SD male rat brain slice (20μm) was incubated with opioid ligand with/without N^3-(2',5'-DiMeOPhAc)-AraU. The radioactivity was measured by LSC and FUJI-FL2000. Bindings of [^3H]DAMGO (μ) and [^3H]DPDPE (δ) displaced by 100uM of N^3-(2',5'-DiMeOPhAc)-AraU, while binding of [^3H]U-69593 did not. Apparent decrease of the binding of μ, and δ receptors was recognized in cortex. In addition m receptor in striatum, hippocampus and thalamus was also decreased. These results indicated that antinociceptive effect of N^3(2',5'-DiMeOPhAc)-AraU was partly contributed μ, and δ opioid receptors.