Molecular structure and function of uridine receptor regulating sleep

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。

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.