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Ten phenothiazine derivatives, substituted in the 2- and 10-positions, were tested as inhibitors of a conditioned avoidance response in rats. The intraperitoneal activities, in decreasing order were: fluphenazine = SQ 10,037 > SQ 4924 = SQ 10,036 > perphenazine > trifluoperazine > thipropazate > triflupromazine > prochlorperazine > chlorpromazine. A CF3 group in position 2 in place of Cl increased activity, and incorporating the N of the side chain in a piperazine ring increased activity still more. A direct comparative study in conditioned rats showed fluphenazine and acetyl-fluphenazine (SQ 4924) to be equally potent and 7 to 9 times as active as triflupromazine. When duration of action was included in the evaluation of activity, fluphenazine and acetylfluphenazine were 25 times as active as triflupromazine. In operant behavior studies in rats, fluphenazine was somewhat slower acting than triflupromazine but was more potent and longer acting. Fluphenazine was 6.5 times as potent as triflupromazine as a “tranquilizer” in hostile rhesus monkeys. The effects of fluphenazine and triflupromazine on behavior and body temperature of dogs were not significantly different. Both drugs reduced spontaneous motor activity, caused sedation and ataxia, and decreased rectal temperature. Cumulative, intravenous doses of fluphenazine or triflupromazine caused slight to moderate hypotension in anesthetized and unanesthetized dogs. Cumulative, intravenous administration of large doses of fluphenazine or triflupromazine to cats caused progressive bradycardia, marked transient hypotension and cardiac arrest. No changes in EEG were noted. At the peak of action, fluphenazine was approximately 4.5 times as potent as triflupromazine as an inhibitor of an elicited head-twitch response in mice. Fluphenazine and triflupromazine caused motor deficits in mice and were equally toxic. In general, fluphenazine (or its acetyl ester) appears to be a more potent and longer-acting tranquilizing agent than any other compound tested and this activity is unattended by corresponding increases in toxic or undesirable autonomic side actions.

2-Amino-5-phenyl-1,3,4-oxadiazole hydrochloride (SQ 4573) was much more active than mephenesin in antagonizing the lethality caused by the intravenous injection of strychnine in mice. The oral median dose causing motor weakness in mice was 39 mg/kg, which is about twice the oral median dose affording protection against lethal injections of strychnine. The results indicate that SQ 4573 is an effective, centrally acting, muscle relaxant with a long duration of action. In dogs and monkeys the prolonged muscle-relaxant effect was well correlated with the slow disappearance of the drug from the plasma. The hepatic damage caused by daily administration of SQ 4573 to dogs and monkeys, although reversible by reduction or discontinuation of dosage, warrants great caution in human pharmacologic trials.

Triflupromazine (TFP) and chlorpromazine (CPZ) exhibited comparable acute toxicities in mice, rats and dogs except following intravenous administration when CPZ was more toxic in mice and less toxic in dogs. In small animals and in in vitro studies measurements of general depressant activity as well as of synergism with or antagonism toward other drugs indicated similar qualitative and quantitative actions for these two phenothiazines. More highly differentiated procedures in rats, monkeys and dogs, however, evidenced the higher potency of TFP as a tranquilizing and antiemetic agent and indicated less likelihood of cardiovascular side actions.