ANTI-EMETIC ACTIVITY OF 4-(2-DIMETHYLAMINOETHOXY)-N-(3,4,5-TRIMETHOXYBENZOYL) BENZYLAMINE HYDROCHLORIDE

¹ Department of Pharmacology, Hoffmann-La Roche, Inc., Nutley 10, New Jersey

This paper compares some effects of 4-(2-dimethylaminmoethoxy) - N -(3,4,5 -trimethoxy- benzoyl) benzylamine hydrochloride (Ro 2-9578, Tigan hydrochloride) with those of chlorpromazine.

Both drugs protected dogs against the emetic effects of apomorphine. Minimum subcutaneous doses abolishing the emetic syndrome produced by 0.1 mg/kg, s.c., of apomorphine were 20 mg/ kg for Ro 2-9578 and 2 mg/kg for chlorpromazine. These doses showed little or no antagonism to emesis induced by intragastric copper sulfate.

Ro 2-9578, in subcutaneous doses of 200 mg/ kg or more, did not depress avoidance behavior in rats. In monkeys, 80 mg/kg, s.c., did not depress the rate of avoidance responding or affect the scores obtained on a behavioral rating scale. Chlorpromazine depressed behavior in each of these tests at an average minimum dose ranging from 0.25 to 1.75 mg/kg.

The activation pattern induced in the EEG of time cat by electrical stimulation of the reticu lar formation was slowed by intravenous chlorpromazine (0.1 mg/kg). Ro 2-9578 at 10 mg/kg showed no such effect.

The duration of the blood pressure fall produced by Ro 2-9578 at 10 mg/kg in the anesthetized dog was less than that produced by chlorpromazine at 1 mg/kg. Ro 2-9578 differed from chlorpromazine in showing no antagonism to the blood pressure effects of epinephrine.

Ro 2-9578 showed no antagonism to the bronchoconstnictor action of histamine in the cat. It caused stimulation of isolated guinea pig ileum, and had no effect on the duration of barbiturate-induced hypnosis in mice.

No signs of toxicity were exhibited by Ro 2-9578 after 13 weeks' daily administration of oral doses up to 120 mg/kg in rats and 100 mg/kg in dogs.

The evidence indicates that Ho 2-9578 is a safe and effective anti-emetic agent of a new type which lacks the sedative properties of chlorpromazine.