Comparison of toxic, anesthetic, and antiacetylcholine activities of piperidyl methadone and its optical isomers

Abstract The l -isomer of piperidyl methadone was found to be the most toxic to mice of the isomers tested. Intraperitoneally the LD 50 value was 34 mg/kg, with the d -isomer and the racemic mixture having slightly larger values. Orally the value was 98 mg/kg, slightly more toxic than the dl -form but markedly more so than the value of 240 mg/kg for the d -isomer. Respiration was less depressed by the d -piperidyl methadone when effects of intraperitoneal LD 50 doses were compared. The l -isomer was also more toxic to growing rats when administered intraperitoneally for many weeks. Doses of 5 mg/kg per day of the l -isomer impaired growth whereas 10 mg/kg per day of the d -isomer had no significant effect on the rats. The toxicity of the dl -form was between those of the individual isomers. The efficiency of food utilization for gain in body weight was in agreement with these values. In producing anesthesia in rats for the first time the l -piperidyl methadone was estimated to be over four times as active as the d -form, over twice as active as the dl -mixture, and some four times as active as morphine. However, on subsequent administrations these differences became somewhat less. Piperidyl methadone or morphine preceding sodium pentobarbital accentuated the stuporous and ataxic recovery period. The isomers of piperidyl methadone studied in isolated guinea pig ileum had antiacetylcholine activities of about 0.7% the activity of an atropine sulfate standard.