Synthesis of N3-Substituted uridine and related pyrimidine Nucleosides and their antinociceptive effects in mice

Seventy eight N-3-substituted derivatives of uridine (1), thymidine (2), 2'-deoxyuridine (3), 6-azauridine (4), 2',3'-O-isopropylideneuridine (5), and arabinofuranosyluracil (6) were synthesized and their antinociceptive effects were evaluated. N-3-(2',4'-Dimethoxyphenacyl)uridine (1l), N-3-(2',4'-dimethoxyphenacyl)2'-deoxyuridine (3l), and N-3-(2',5'-dimethoxyphenacyl)arabinofuranosyluraciI (6m) possessed 93, 86, and 82% of the antinociceptive effects tested by hot plate, respectively. The antinociceptive effects of three derivatives were 5.8, 5.4, and 5.1-folds of the effect of N-3-phenacyluridine (1h) (16%), respectively. The structure-activity relationship of N-3-substituted pyrimidine nucleosides was also discussed.