Central depressant effects of N3-substituted 6-azauridines in mice.
Central depressant effects of N3-substituted 6-azauridines in mice.
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N3 取代的 6-氮杂苷对小鼠的中枢抑制作用。
DOI：
10.1248/cpb.39.2597
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发表时间：
1991
影响因子：
1.7
通讯作者：
I. Yamamoto
中科院分区：
文献类型：
--
作者：
M. Koshigami;K. Watanabe;T. Kimura;I. Yamamoto
通过脑室内 (i.c.v.) 注射检查 N3 取代的 6-氮杂苷 (6-AzUd) (1) 对小鼠的中枢抑制作用。合成了1的N3位上的烷基、苄基、二甲苯基和苯乙基取代等11种衍生物，并以催眠活性、运动活性、运动不协调性和戊巴比妥诱导的睡眠延长为指标评价其药理作用。 12 种化合物中有 6 种显示出催眠活性。在剂量为 2 微摩尔/小鼠时，1, N3-benzyl-6-AzUd (7)、N3-o-xylyl-6-AzUd (8)、N3-m-xylyl-6-AzUd (9)、N3-p-xylyl-6-AzUd (10) 和 N3-α-苯乙基-6-AzUd (11) 诱导的平均睡眠时间为分别为 14、11、45、12、9 和 16 分钟。这些衍生物和 N3-β-苯乙基-6-AzUd (12)（1.5 μmol/小鼠）显着延长戊巴比妥诱导的（40 mg/kg，腹腔注射）睡眠时间，而 N3-烷基化衍生物（甲基、乙基、正丙基、正丁基和烯丙基取代）均未发挥催眠活性或戊巴比妥诱导的睡眠延长。核苷1及其二甲苯衍生物（1.5μmol/小鼠）显着降低小鼠的运动活性，其作用与催眠活性平行。这些化合物（1.5 微摩尔/小鼠）也会产生运动不协调，并增强地西泮诱导的运动不协调的效果。这些结果表明，1 及其苄基相关衍生物（而非烷基衍生物）对中枢神经系统具有抑制作用。
Central depressant effects in mice of N3-substituted 6-azauridines (6-AzUd) (1) were examined by intracerebroventricular (i.c.v.) injection. Eleven derivatives including alkyl-, benzyl-, xylyl- and phenylethyl-substitution onto the N3-position of 1 were synthesized and their pharmacological effects were evaluated using hypnotic activity, locomotor activity, motor incoordination and pentobarbital-induced sleep prolongation as indices. Six of 12 compounds showed the hypnotic activity. At a dose of 2 mumol/mouse, the mean sleeping time induced by 1, N3-benzyl-6-AzUd (7), N3-o-xylyl-6-AzUd (8), N3-m-xylyl-6-AzUd (9), N3-p-xylyl-6-AzUd (10) and N3-alpha-phenylethyl-6-AzUd (11) was 14, 11, 45, 12, 9 and 16 min, respectively. These derivatives and N3-beta-phenylethyl-6-AzUd (12) (1.5 mumol/mouse) significantly prolonged pentobarbital-induced (40 mg/kg, i.p.) sleeping time, whereas none of the N3-alkylated derivatives (methyl-, ethyl-, n-propyl-, n-butyl- and allyl-substitution) exerted the hypnotic activity or pentobarbital-induced sleep prolongation. Nucleoside 1 and its xylyl-derivatives (1.5 mumol/mouse) significantly decreased locomotor activity of mice, their effects paralleled the hypnotic activity. These compounds (1.5 mumol/mouse) also produced motor incoordination and potentiated the effect of diazepam-induced motor incoordination. These results indicate that 1 and its benzyl-related derivatives, but not alkyl-derivatives have a depressant effect on the central nervous system.