Central nervous system depressant effects of N3-substituted derivatives of deoxyuridine in mice.
Central nervous system depressant effects of N3-substituted derivatives of deoxyuridine in mice.
复制标题
脱氧尿苷 N3 取代衍生物对小鼠的中枢神经系统抑制作用。
DOI：
10.1248/bpb.19.142
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发表时间：
1996
影响因子：
2
通讯作者：
I. Yamamoto
中科院分区：
文献类型：
--
作者：
T. Kimura;J. Kuze;S. Teraoka;K. Watanabe;Y. Tateoka;S. Kondo;I. Ho;I. Yamamoto
合成了脱氧尿苷（1）的N ~ 3位取代衍生物，并通过侧脑室注射（i. c. v.）小鼠注射。包括甲基（2）、乙基（3）、丙基（4）、烯丙基（5）、丁基（6）、苄基（7）、邻、间、对二甲苯基等11个衍生物（8，9，10），α-苯乙基（11）和苯甲酰甲基（12）衍生物，并通过使用催眠活性，戊巴比妥诱导的睡眠延长，自发活动和运动不协调作为中枢神经系统（CNS）损伤效应的指标。在2.0 μ mol/只小鼠的剂量下，7、8、9和10诱导的平均睡眠时间值分别为23、35、29和30 min。尽管烷基（2-6）衍生物没有引起任何催眠活性，但一些测试的衍生物（3、5、6、8-12）显著延长了戊巴比妥诱导的睡眠时间。当苯甲酰甲基取代的1的CNS抑制作用与其它氧代嘧啶核苷比较时，N3-苯甲酰甲基尿苷（13）、N3-苯甲酰甲基胸苷（14）、N3-苯甲酰甲基-6-氮杂尿苷（15）、化合物12、13和14（1.0 μ mol/小鼠，i. c. v.）显著降低小鼠自发活动。此外，12-15（1.0 μ mol/小鼠，i. c. v.）导致老鼠运动失调这些结果表明，脱氧尿苷衍生物一般具有中枢催眠活性，苄基和二甲苯基衍生物具有催眠活性，而烷基衍生物没有。
N3-Substituted derivatives of deoxyuridine (1) were synthesized and their pharmacological effects were evaluated by intracerebroventricular (i.c.v.) injection in mice. Eleven derivatives, including the methyl (2), ethyl (3), propyl (4), allyl (5), butyl (6), benzyl (7), o, m and p-xylyls (8, 9, 10), alpha-phenylethyl (11) and phenacyl (12) derivatives, of 1 were prepared and their pharmacological effects were evaluated by using hypnotic activity, pentobarbital-induced sleep prolongation, spontaneous activity and motor incoordination as indices of central nervous system (CNS) depressant effects. At a dose of 2.0 mumol/mouse, the values of mean sleeping time induced by 7, 8, 9 and 10 were 23, 35, 29 and 30 min, respectively. Although the alkyl (2-6) derivatives did not cause any hypnotic activity, some derivatives tested (3, 5, 6, 8-12) significantly prolonged the pentobarbital-induced sleeping time. When the CNS depressant effects of phenacyl substituted 1 were compared to that of other oxopyrimidine nucleosides, N3-phenacyluridine (13), N3-phenacylthymidine (14), N3-phenacyl-6-azauridine (15), compounds 12, 13 and 14 (1.0 mumol/mouse, i.c.v.) significantly decreased mouse spontaneous activity. Furthermore, 12-15 (1.0 mumol/mouse, i.c.v.) caused mouse motor incoordination. These results indicate that deoxyuridine derivatives have generally central depressant activity, and the benzyl and xylyl derivatives, but not alkyl derivatives, possess hypnotic activity.