N-substituted oxopyrimidines and nucleosides: structure-activity relationship for hypnotic activity as central...

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.