Central nervous actions of new neuroleptics, dibenzoazepine derivatives.

Abstract

Using unanesthetized mice and rabbits, actions of 2-chloro-11-(4-methylpiperazino)dibenzo-[b,f] [1,4]oxazepine (I) on the central nervous system were studied, in comparison with those of chlothiapine (II) and perphenazine (III). I, II, and III induced marked sedation and catalepsy at various doses in rats (1.apprx.200 mg/kg, per os) and in rabbits (1.apprx.7 mg/kg, i.v.). Large doses of I and II sometimes caused convulsion to death. ED50 of the compds. which induced catalepsy in mice was 0.34(I), 0.35(II), and 2.75(III) mg/kg. ED50 of the compds. on the analgesic action, measured by no. of stretching after benzoquinone, was 0.66(I), 2.15(II), and 4.60(III) mg/kg. Inhibitory effect of I on the traction test of mice was the most potent among the 3, followed by II and III in this order. I also inhibited the conditioned avoidance response of mice (ED50 = 0.075 mg/kg, per os). All 3 compds. enhanced the convulsion by elec. stimulation of mice. Anti-tremorine activity was shown with ED50 in the order 6.4(I), 4.0(II), and 5.2(III) mg/kg. On the electroencephalogram (EEG) of rabbits with chronically implanted electrodes, I induced high-voltage slow waves in the cortex, dissocn. of neocortical waves from hippocampal waves, and spike discharges, whereas II induced all these changes to a less degree, and III induced only slow waves in EEG. Two to .apprx.5 mg/kg of the 3 compds. (i.v.) inhibited the arousal response of EEG after stimulation at the reticular ascending activating system and the posterior hypothalamic area, but did not affect the recruiting response by stimulation of the thalamus. I (2 mg/kg i.v.), II, and III (5 mg/kg i.v.) enhanced seizure discharge by stimulation of the dorsal hippocampus and the amygdala. I and II were considered to possess central nervous actions similar to III. [on SciFinder (R)]