Abstract
The pharmacological potency, absorption, distribution and excretion of N3-benzylthymidine (N3-ByTd), a new type of hypnotics, were studied in mice.
N3-Substituted thymidine derivative, N3-o, m or p-xylylthymidine, N3-m-chlorobenzylthymidine, were synthesized. Furthermore, the sugar moiety of certain derivatives was methylated. N3-ByTd and its derivatives were evaluated for hypnotic activity by intracerebroventricular (i.c.v.) administration as central depressants. N3-ByTd (2.0μmol/mouse) induced 72min lasting sleeping time by i.c.v. injection. The hypnotic activity of N3-ByTd was highest among the compounds tested. N3-ByTd also produced the decrease of mice spontaneous activity by i.v., p.o. and i.p. injection.
[3H] N3-ByTd was administered i.v. (300mg, 5.5MBq/kg) or p.o. (300mg, 7.1MBq/kg) to mice. Brain, plasma, liver, muscle, adrenal, thymus, spleen, kidney, testis, epididymis, fat and lung of the mouse were collected and then the radioactivity in each tissue was measured. The concentration of [3H] N3-ByTd decreased in two phases in the most of tissue. Trace amount of [3H]N3-ByTd was distributed to the brain, suggesting an ability to penetrate through the blood brain barrier from peripheral. The concentration of [3H] N3-ByTd in the liver and kidney were higher than that in the plasma after i.v. administration, and maximum concentration in these organs corresponded to 5.8 and 1.9% of total injection, respectively. In urine, 46.1%(i.v.) and 54.5% (p.o.) of total radioactivity were excreted within 48 hours after the administrations.
N3-Benzylthymine (N3-ByT), thymidine (Td) and thymine (T) were identified as the metabolites in the brain, liver and urine. The possible metabolic pathway of N3-ByTd is suggested to be N3-debenzylation and N3-deribosylation. It appears that N3-ByTd itself is a real hypnotic substance in mice, since these metabolites did not have any hypnotic activity.
Although incorporation of [3H] N3-ByTd into nucleic acid was also examined, there was no incorporation of 3H into RNA and DNA. N3-ByTd may effect on central nervous system as a hypnotic, but not by an endogenous compound.
