Molecular structure and function of uridine receptor regulating sleep

调节睡眠的尿苷受体的分子结构和功能

• 批准号: 13672311
• 负责人: KIMURA Toshiyuki
• 金额: $ 2.3万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672311/
• 关键词: uridine; sleep; Uridine receptor; antinociception; nucleoside; Central nervous system; receptor

The pyrimidine nucleosides including uridine are known to have central nervous system (CNS) depressant effects, such as hypnotic activity in mice. N^3-Benzyl and phenacyl derivatives of pyrimidine nucleosides were synthesized and their pharmacological effects on the CNS have been studied by intracerebroventricular injection to mice. We have found that N^3-benzyl or phenacyl substituted uridine and arabinofuranosyluracil exert antinociceptive activity in mice at a dose of 500 nmol/mouse. Systematic studies on structure-activity relationship of uridine related derivatives were performed to find stronger antinociceptive compounds, so that certain derivatives such as o- or p-fluorobenzyl-, o, m, p-chlo ; robenzyl-, o, m, p-bromobenzyl, p-chlorophenacyl substituted arabinofuranosyluracils exhibited 12-58 min of mice sleeping time. Moreover, o-fluorobenzyl- and o, p-bromobenzyl-arabinofuranosyluracils significantly potentiated pentobarbiral-induced sleep. Especially, p-chloro and p-bromo phenacyl derivatives exerted more potent antinociceptive activity than that of N^3-phenacyluridine. However, none of the N^3-benzyluridine derivatives except for N^3-(p-chlorobenzyl)uridine showed the antinociceptive activity. N^3-(2', 5' -dimethoxyphenacyl)uridine also exerted antinociceptive activities in mice. N^3-Phenacyluridine-6-carbonic acid was coupled with Affigel 102 and carbodiimide to prepare affinity column for using prurification of uridine receptor.

已知嘧啶核苷包括尿苷具有中枢神经系统（CNS）抑制作用，例如小鼠中的催眠活性。本文合成了嘧啶核苷的N^3-苄基和苯甲酰甲基衍生物，并通过小鼠侧脑室注射研究了它们对中枢神经系统的药理作用。我们已经发现，N^3-苄基或苯甲酰甲基取代的尿苷和阿拉伯呋喃糖基尿嘧啶在500 nmol/小鼠的剂量下在小鼠中发挥抗伤害感受活性。对尿苷类衍生物的构效关系进行了系统的研究，以寻找更强的抗伤害性化合物，某些衍生物如邻-或对-氟苄基-，邻，间，对-氯苯甲基-，邻，间，对-溴苄基，对-氯苯甲酰甲基取代的阿拉伯呋喃糖基尿嘧啶显示出12-58 min的小鼠睡眠时间。此外，o-氟苄基-和o，p-溴苄基-阿拉伯呋喃糖基尿嘧啶显着增强戊巴比妥诱导的睡眠。特别是对氯苯甲酰甲基和对溴苯甲酰甲基衍生物比N^3-苯甲酰甲基尿苷具有更强的抗伤害活性。然而，除了N^3-（对氯苄基）尿苷外，没有N^3-苄基尿苷衍生物显示出抗伤害感受活性。N^3-（2 '，5' -二甲氧基苯甲酰甲基）尿苷在小鼠中也表现出抗伤害感受活性。将N，3-苯甲酰尿苷-6-碳酸与Affigel 102和碳二亚胺偶联，制备亲和柱，用于纯化尿苷受体。

项目成果

K. Watanabe, T. Matsunaga, T. Kimura, T. Funahashi, Y. Funae, T. Ohshima, I. Yamamoto: "Major cytochrome P450 enzyme responsible for aldehyde oxygenation of 11-oxo-□^8-tetrahydrocannabinol and 9-anthralaldehyde in human liver"Drug Metabolism and Pharmacok

K. Watanabe、T. Matsunaga、T. Kimura、T. Funahashi、Y. Funae、T. Ohshima、I. Yamamoto：“主要细胞色素 P450 酶负责 11-oxo-□^8-四氢大麻酚和 9-人体肝脏中的蒽醛《药物代谢与药理学》

T.Kimura, I.K.Ho, I.Yamamoto: "Uridine receptor : Discovery and its involvement in sleep mechanism"Sleep. 24. 251-260 (2001)

T.Kimura、I.K.Ho、I.Yamamoto：“尿苷受体：发现及其参与睡眠机制”睡眠。

S. Kozai, T. Maruyama, T. Kimura, and I. Yamamoto: "Synthesis and hypnotic activities of 4-thio analogues of N^3-substituted uridines"Chem. Pharm. Bull.. 49. 1185-1188 (2001)

S. Kozai、T. Maruyama、T. Kimura 和 I. Yamamoto：“N^3-取代尿苷的 4-硫代类似物的合成和催眠活性”Chem。

T.Kimura, M.Miki, M.Ikeda, S.Yonemoto, K.Watanabe, S.Kondo, I.K.Ho, I.Yamamoto: "Possible existence of a novel receptor for undine analogues in the central nervous system using two isomers, N3-(S)-(+)-and N3-(R)-(-)-a-phenethyl-b-hydroxyuridines"Biol. Pha

T.Kimura、M.Miki、M.Ikeda、S.Yonemoto、K.Watanabe、S.Kondo、I.K.Ho、I.Yamamoto：“中枢神经系统中可能存在一种新的 undine 类似物受体，使用两种异构体，

K. Watanabe, M. Matsuda, S. Furuhashi, T. Kimura, T. Matsunaga, and I. Yamamoto: "Skin reaction induced by aldehydes for food flavoring agents"J. Health. Sci.. 47. 327-329 (2001)

K. Watanabe、M. Matsuda、S. Furuhashi、T. Kimura、T. Matsunaga 和 I. Yamamoto：“食品调味剂醛类引起的皮肤反应”J.