Metabolism of a novel hypnotic, N³-phenacyluridine, and hypnotic and sedative activities of its enantiomer metabolites in mouse

Abstract

1. The metabolism of N³-phenacyluridine (3-phenacyl-1- beta-D-ribofuranosyluracil), a potent hypnotic nucleoside derivative, was studied in mouse. 2. Of the radioactivity, 65% was excreted in urine within 48 h after intraperitoneal (i.p.) administration of [³H] N³-phenacyluridine. The urinary metabolites N³-phenacyluracil and N³-alpha-hydroxy-beta-phenethyluridine were extracted, isolated and analyzed by mass spectrometry. 3. Racemates of N³-alpha-hydroxy-beta-phenethyluridine were synthesized and both isomers were separated as N³-(S)-(+)-alpha-hydroxy-beta-phenethyluridine and N³-(R)-(-)-alpha hydroxy-beta-phenethyluridine by hplc (CHIRALCEL-OJ column) with retentions of 13.8 and 17.9 min respectively. The reduction process took place with high stereo-selectivity, which gave an alcohol product in the urine with the same retention (17.9 min) as one of the synthetic isomers separated by hplc. 4. One of urinary metabolites was identified as N³-(S)-(+)-alpha-hydroxy-beta-phenethyluridine. N³-phenacyluridine was predominantly converted to an alcoholic metabolite of (S)-(+)-configuration. 5. N³-phenacyluracil and uridine were also identified as minor metabolites. 6. The pharmacological effects of the metabolites and related compounds were also evaluated in mouse. N³-(S)-(+)-alpha-hydroxy-beta-phenethyluridine, but not N ³-(R)-(-)-alpha hydroxy-beta-phenethyluridine, possessed hypnotic activity and potentiated pentobarbitalinduced sleeping time with a similar potency to the parent compound, N³-phenacyluridine. N³-alpha-hydroxy-beta-phenethyluridine (racemate) had almost two thirds of the hypnotic activity of N³-(S)-(+)- alpha-hydroxy-beta-phenethyluridine. No other metabolites exhibited hypnotic activities. 7. The present study indicates that N³-(S)-(+)-alpha-hydroxy-beta-phenethyluridine, a major metabolite of N³-phenacyluridine, is an active metabolite and contributes a significant CNS depressant effect.