Central nervous system depressant effects of N3-substituted derivatives of deoxyuridine in mice.

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.