Abstract

1. Analgesic studies on six members of the morphinan series confirmed the fact that levorphan has twice the potency of racemorphan. The methyl ether, levomethorphan, also was found to have twice the activity of its racemate, racemethorphan. These methyl ethers had one-tenth the potency of the corresponding parent compounds. The dextro-rotatory isomers, dextrorphan and dextromethorphan, were found to have negligible, if any, analgesic activity.

2. Acute toxicity tests showed that the levo-rotatory isomers were more toxic than their corresponding racemates. These in turn were more toxic than their dextro-rotatory forms. The methyl ethers were more toxic than the parent compounds. Chronic toxicity studies have been carried out in rats and dogs on the racemates and in rats on levorphan and dextromethorphan.

3. Respiratory studies showed that the depressant characteristics of the racemates were due to the levo-rotatory isomers. The dextro-rotatory forms had little effect.

4. Antitussive studies demonstrated that the levo-rotatory isomers and the racemates were cough inhibitors but only so in doses that produced lethargy, ataxia or sleep. The dextro-rotatory isomers, particularly dextromethorphan, exerted significant antitussive activity without inducing such effects.

5. Levorphan is of interest because it has twice the analgesic potency of racemorphan but is not twice as toxic. Dextromethorphan is of interest because it possesses high antitussive activity without associated analgesia and cerebral depression.