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

已知N^3-取代氧嘧啶核苷具有中枢神经系统抑制作用，如催眠活性和抗伤害性作用。我们合成了N^3-取代的氧代嘧啶核苷，如苄基、苯乙酰及其相关的基团取代类似物。N^3-硝基苄基和N^3-(2‘-氰基苯基)-阿拉伯呋喃尿苷对小鼠有较强的催眠作用，给药剂量为2.0umol/只。注射。N^3-(2‘，5’-Dimethoxyphenacyl)-arabinofuranosyluracil(N^3-(2‘，5’-DiMeOPhAc)-Arau)对小鼠无催眠作用，但具有抗伤害性作用，该作用可被纳洛酮抑制。我们用大鼠脑片研究了N^3-(2‘，5’-DiMeOPhAc)-Arau与阿片受体的相互作用。SD雄性大鼠脑片(20μm)与阿片配体孵育，加入或不加入N^3-(2‘，5’-DiMeOPhAc)-Arau。用LSC和FUJI-FL2000进行放射性测量。用100微米的N^3-(2‘，5’-DiMeOPhAc)-Arau取代[^~3H]DAMGO(μ)和[^~3H]DPDPE(δ)的结合，而与[^~3H]U-69593的结合没有改变。皮质中μ和δ受体的结合明显减少。此外，纹状体、海马和丘脑的m受体也减少。这些结果表明，N^3(2‘，5’-DiMeOPhAc)-Arau的抗伤害性作用部分与μ和δ阿片受体有关。

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.