Pharmacology of amezinium, a novel antihypotensive drug. VI. Effect on central nervous functions.

: 4-Amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in this study briefly called amezinium, was tested for possible central effects taking particular account of the mechanisms of action found for this substance in other studies. 1. The most conspicuous action of amezinium was in modifying reserpine-induced ptosis and reserpine-induced hypothermia. When amezinium is given before reserpine, the ED50 values are 0.15 and 3.9 mg/kg p.o. for both mouse and rat. These effects can be explained by a peripheral site of action since peripheral sympathomimetic effects can also be demonstrated in this dose range. Higher doses (10 mg/kg and upwards p.o.) were required to abolish reserpine-induced hypothermia 17 h after reserpine administration, an effect which probably requires a central site of action. But for imipramine, desipramine and pargyline the effective doses are the same in both experimental models (administration before and after reserpine, respectively). 2. Amezinium potentiated the effect of a threshold dose of L-dopa. Based on the central symptoms, higher doses (10 mg/kg p.o.) were also required for this effect. 3. With blood pressure increasing doses, the sleeping-waking pattern was modified in that duration and number of REM-episodes were reduced; in cats there was no parallel increase of wakefulness whilst in rats there was a slight relative increase of wakefulness. 4. Amezinium, particularly at high doses (46.4 mg/kg and upwards), exhibited a central depressant effect on the spontaneous behaviour of mice and rats and on orientational hyperactivity of mice. Based on the modification of aggregation toxicity, the effect of methamphetamine was reduced. In no dose range was there any evidence of methamphetamine-like effects (increase of motor activity, inhibition of food intake and increase of aggregation toxicity). 5. Amezinium did not affect the duration of hexobarbital anaesthesia or the coordination of mice on a rotating rod. 6. The acute toxicity of amezinium in mice and rats was low. The oral LD50 for mice was 1630 mg/kg and for rats 1410 mg/kg.