Synthesis of N3-Substltuted Uridine and Related Pyrimidine Nucleosides and Their Antinociceptive Effects in Mice

Seventy eight N3-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. N3-(2',4'-Dimethoxyphenacyl)uridine (11), N3-(2',4'-dimethoxyphenacyl)2'-deoxyuridine (31), and N3-(2',5'-dimethoxyphenacyl)arabinofuranosyluracil (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 N3-phenacyluridine (1h) (16%), respectively. The structure-activity relationship of N3-substituted pyrimidine nucleosides was also discussed.