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

N3取代氧代嘧啶类药物的催眠和抗伤害作用及其机制

• 批准号: 15590075
• 负责人: KIMURA Toshiyuki
• 金额: $ 1.98万
• 依托单位: Hokuriku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590075/
• 关键词: uridine; sleep; antinociceptive effect; nucleoside; uridine receptor; central nervous system

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.

已知N^3-取代的氧代嘧啶核苷具有中枢神经系统抑制作用，例如催眠活性和抗伤害作用。我们合成了N^3取代的氧代嘧啶核苷，例如苄基、苯甲酰基及其相关基团取代的类似物。 N^3-Nitrobenzyl 和 N^3-(2'-cyanobenzyl)-arabinofuranosyluracil 在 2.0 umol/小鼠的静脉注射中具有强催眠活性。注射。 N^3-(2',5'-Dimethoxyphenacyl)-arabinofuranosyluracil (N^3-(2',5'-DiMeOPhAc)-AraU) 被发现对小鼠具有镇痛作用，但没有催眠活性，并且该作用被纳洛酮抑制。我们使用大鼠脑切片报告了 N^3-(2',5'-DiMeOPhAc)-AraU 与阿片受体的相互作用。 SD雄性大鼠脑切片（20μm）与阿片类配体（含/不含N^3-(2',5'-DiMeOPhAc)-AraU）一起孵育。通过LSC和FUJI-FL2000测量放射性。 [^3H]DAMGO (μ) 和 [^3H]DPDPE (δ) 的结合被 100uM 的 N^3-(2',5'-DiMeOPhAc)-AraU 取代，而 [^3H]U-69593 的结合则没有。在皮质中发现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的镇痛作用部分归因于μ和δ阿片受体。

项目成果

Synthesis of N^3-substituted uridine and related pyrimidine nucleosides and their antinociceptive effects in mice

N^3取代尿苷及相关嘧啶核苷的合成及其对小鼠的镇痛作用

• 发表时间: 2005
• 期刊: Chem.Pharm.Bull. 53
• 作者: T.Shimizu;T.Kimura;T.Funahashi;K.Watanabe;I.K.Ho;I.Yamamoto
• 通讯作者: I.Yamamoto

N^3-Phenacyluridine as a new type of antinociceptive compound in mice

N^3-Phenacyuridine 作为一种新型小鼠抗伤害化合物

• 发表时间: 2003
• 期刊: Res.Commun.Mol.Pathol.Pharmacol. 113
• 作者: T.Kimura;T.Shimizu;T.Funahashi;M.Nagakura;K.Watanabe;K.Tachibana;S.Kondo;I.K.Ho;I.Yamamoto
• 通讯作者: I.Yamamoto