Molecular structure and function of uridine receptor regulating sleep

包括尿苷在内的嘧啶核苷已知具有中枢神经系统（CNS）抑制作用，如对小鼠的催眠活性。合成了N^3-苄基和苯那基嘧啶核苷衍生物，并通过小鼠脑室注射研究了它们对中枢神经系统的药理作用。我们发现N^3-苄基或phenacyl取代尿嘧啶和阿拉伯糖脲嘧啶在500 nmol/只小鼠剂量下对小鼠具有抗伤性活性。对尿苷相关衍生物的构效关系进行了系统的研究，以发现更强的抗伤性化合物，因此某些衍生物如o-或对氟苯-，o, m，对氯；Robenzyl -, o, m，对溴苄基，对氯苯酰基取代阿拉伯糖脲嘧啶的小鼠睡眠时间为12-58 min。此外，邻氟苯和邻溴苄基阿拉伯糖脲嘧啶显著增强戊巴比拉诱导的睡眠。特别是，对氯和对溴苯基衍生物比N^3-苯基尿嘧啶具有更强的抗伤活性。除N^3-（对氯苯）尿嘧啶外，其余N^3-苄基尿嘧啶衍生物均无抗伤活性。N^3-（2', 5' -二甲氧基苯那基）尿苷在小鼠中也有抗伤害感受活性。N^3- phenacyluridine -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.