N-substituted oxopyrimidines and nucleosides: structure-activity relationship for hypnotic activity as central nervous system depressant.
N-substituted oxopyrimidines and nucleosides: structure-activity relationship for hypnotic activity as central nervous system depressant.
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N-取代的氧代嘧啶和核苷：作为中枢神经系统抑制剂的催眠活性的结构-活性关系。
作者：
I. Yamamoto;T. Kimura;Y. Tateoka;K. Watanabe;I. Ho
合成了N-3-苄基尿苷（3-（苯甲基）-1-β-D-呋喃核糖基尿嘧啶）（1f）及其相关化合物，并评价了其作为中枢抑制剂的催眠活性。一级结构修饰已在尿苷中嘧啶环的N3位进行。侧脑室注射N ~ 3-苄基取代尿苷对小鼠有催眠作用，并可引起戊巴比妥（PB）的睡眠效应。根据该结果，进行二次改性，即，将苄基转化为苄基类似基团。这些化合物也显示出催眠活性，但它们的强度不同。第三，改变糖部分进行了研究，但发现这是必要的催眠活性。在一般情况下，在尿苷的N3位引入苄基类似基团增加了催眠活性，糖部分的修饰降低了活性。静脉（iv）给药未能表明催眠活性的大多数化合物测试。然而，修饰的糖，如2 '，3'，5 '-三-O-甲基或乙酰基衍生物的1f引起的催眠活性，通过静脉注射。大多数化合物被发现显示出增强PB诱导的睡眠，并且它们的作用与催眠活性平行。结果清楚地表明，分别在N3和N1位置的苄基和β-D-呋喃核糖基是催眠活性所必需的。两种效应的化学结构的关键部分似乎是尿苷部分。
N3-Benzyluridine (3-(phenylmethyl)-1-beta-D-ribofuranosyluracil) (1f) and its related compounds were synthesized and evaluated for hypnotic activity as central depressants. The primary structural modification has been carried out at the N3 position of the pyrimidine ring in uridine. N3-Benzyl-substituted uridine exhibited hypnotic activity as well as pentobarbital (PB) induced sleep effect on mice when administered by intracerebroventricular (icv) injection. From this result, the secondary modification was performed, namely, converting the benzyl group into a benzyl analogous group. These compounds also showed hypnotic activity, but their intensities were varied. Thirdly, changing the sugar moiety was investigated; however, it was found to be necessary for hypnotic activity. In general, introduction of benzyl analogous groups at the N3 position of uridine increased the hypnotic activity, and modification of the sugar moiety decreased the activity. Intravenous (iv) administration failed to indicate hypnotic activity in most of the compounds tested. However, modified sugars such as 2',3',5'-tri-O-methyl or -acetyl derivatives of 1f elicited hypnotic activity by iv injection. The majority of compounds were found to show potentiation of the PB-induced sleep, and their effects were in parallel with the hypnotic activity. The result clearly indicates that the benzyl group and beta-D-ribofuranosyl, at the N3 and N1 positions, respectively, are necessary for hypnotic activity. The critical portion of the chemical structure for both effects appears to be the uridine moiety.