Studies on 6-azauridine and 6-azacytidine—II.: The effects of 6-azauridine on the central nervous system

Abstract

The effects of 6-azauracil and its ribonucleoside—6-azauridine—on the central nervous system were compared in mice. It was shown that loss of the righting reflex, motor inco-ordination and analgesia are rather subtoxic effects, the values for the ed 50 being close to those of the ld 50 of both compounds. The antagonism towards various convulsant agents appears to be more specific, especially as antagonism to nicotine is concerned. The most sensitive indicator of central activity of both 6-azapyrimidines was found in the depression of exploratory activity in mice and rats. Conditioned avoidance behaviour was unaffected at very high doses. In all these tests the difference between 6-azauracil and 6-azauridine was only quantitative, the ribonucleoside being 2–4 times less active on a molar basis than the free base; however, the 50 to 100-fold increase in the activity of 6-azauridine after its direct injection into the cerebral ventricles of mice and cats, in which a typical behavioural pattern is evoked, suggests that penetration through the hemato-encephalic barrier is an important limiting factor with respect to the potentiality of 6-azauridine for exerting an action on the central nervous system. Qualitatively identical effects have been observed after intraventricular injection of 6-azauridine-5'-monophosphate and small amounts of this nucleotide have been detected in various regions of the cat brain after administration of 14C-labelled 6-azauridine into the cerebral ventricles. The possibility is discussed that central activity and carcinostatic effects of 6-azauracil and 6-azauridine are based on a common biochemical mechanism, namely inhibition of orotidylic acid decarboxylase resulting from the formation of 6-azauridine-5'-monophosphate.