Yamamoto I, Kimura T, Tateoka Y, Watanabe K, Ho I K
Department of Hygienic Chemistry, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
J Med Chem. 1987 Dec;30(12):2227-31. doi: 10.1021/jm00395a009.
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.
N3-苄基尿苷（3-(苯甲基)-1-β-D-呋喃核糖基尿嘧啶）（1f）及其相关化合物被合成，并作为中枢抑制剂评估其催眠活性。主要的结构修饰是在尿苷嘧啶环的N3位进行的。N3-苄基取代的尿苷通过脑室内（icv）注射给药时，对小鼠表现出催眠活性以及戊巴比妥（PB）诱导的睡眠效应。基于此结果，进行了二次修饰，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，但强度有所不同。第三，研究了糖部分的变化；然而，发现这对催眠活性是必要的。一般来说，在尿苷的N3位引入苄基类似基团会增加催眠活性，而糖部分的修饰会降低活性。静脉注射（iv）给药在大多数测试化合物中未显示出催眠活性。然而，1f的2',3',5'-三-O-甲基或-乙酰基衍生物等修饰糖通过静脉注射引发了催眠活性。大多数化合物被发现对PB诱导的睡眠有增强作用，且它们的作用与催眠活性平行。结果清楚地表明，分别位于N3和N1位的苄基和β-D-呋喃核糖基对催眠活性是必要的。两种效应的化学结构关键部分似乎是尿苷部分。
