Pharmacological studies on timiperone, a new neuroleptic drug Part II: General pharmacological properties.

General pharmacological properties of 4'-fluoro-4-[4-(2-thioxo-1-benzimidazolinyl) piperidino] butyrophenone (timiperone), a new neuroleptic drug, were compared with those of haloperidol. 1. Central nervous system: In behavioral observation, timiperone showed a typical neuroleptic profile at doses of 0.1 mg/kg p.o. and more (mice). The drug produced a moderate hypothermia at 10 mg/kg p.o. (rabbits), a mild increase in pain threshold at 3 mg/kg p.o. (mice and rats) and a slowing of cortical EEG at 1 mg/kg i.v. (cats). ED50 values of drug for the potentiation of ether and alcohol anesthesia were 0.34 and 0.22 mg/kg p.o., respectively (mice). Timiperone ahd neither an anticonvulsant activity at 30 mg/kg p.o. (mice) nor an effect on the spinal reflex at 1 mg/kg i.v. (cats). These effects of timiperone on the central nervous system were almost similar to those of haloperidol. 2. Respiratory and cardiovascular system: At dose of 0.03 mg/kg i.v. and more, timiperone produced transient increases in respiratory rate and regional arterial blood flow which were accompanied by a fall in blood pressure (dogs). Haloperidol had qualitatively similar effect, but was weaker than timiperone. Both drugs at high concentration (3X10-6 g/ml) exerted negative inotropic and chronotropic effect in isolated atrial preparations (guinea-pigs), and non-competitively antagonized the positive chronotropic action of isoprenaline. Atropine (2.5X10-7 g/ml) failed to modify the chronotropic action of timiperone (3X10-6 g/ml). 3. Autonomic nervous system: Timiperone at 0.1 mg/kg p.o. and haloperidol at 0.3 mg/kg p.o. induced a moderate miosis (rabbits) and antagonized blood responses to noradrenaline and acetylcholine (dogs). Both drugs at 1 mg/kg i.v. had no ganglion-blocking activity (cats). 4. Smooth muscle: In isolated guinea-pig ileum and vas deferens, timiperone and haloperidol (10-5 g/ml) antagonized the contractile responses of the muscles to various spasmogens, Both drugs at approximately 10-6 g/ml decreased spontaneous motility of the isolated rat uterus and inhibited the gastric secretion at 1 mg/kg i.p. (rats). At high doses, both drugs inhibited the gastrointestinal propulsion (mice), motility (dogs) and gastric emptying rate (rats), and had no damaging effect on the gastric mucosa (rats). 5. Skeletal muscle: At 0.1 mg/kg i.v., timiperone and haloperidol slightly enhanced twitch response of the anterior tibial muscle to electrical stimulation (rabbits). 6. Urine volume and urinary electrolytes: Timiperone and haloperidol showed a diuretic effect at 3 mg/kg p.o. whereas they inhibited urine output and electrolytes excretion at 30 mg/kg p.o. (rats).