ANTAGONISM OF MORPHINE-INDUCED RESPIRATORY DEPRESSION AND ANALGESIA AND INHIBITION OF NARCOTIC N-DEMETHYLATION IN VITRO BY N-SUBSTITUTED ANALOGUES OF l-3-HYDROXYMORPHINAN AND BY N-ALLYL-NORMORPHINE

¹ Department of Pharmacology and Toxicology, The University of Wisconsin, Medical Sciences Building, Madison, Wisconsin

The antimorphine properties of a series of N-substituted 3-hydroxymorphinans and of nalorphine were studied. Respiratory effects were measured in the rabbit, analgesic effects were observed in the rat, and the inhibition of the liver microsomal N-demethylation of narcotic drugs by these compounds was studied in the rat and the mouse. The following N-substituted 3-hydroxymorphinan derivatives were employed: methyl, ethyl, propyl, 2'-hydroxypropyl, 3'-hydroxypropyl, allyl, acetonyl and propargyl. 3-Hydroxymorphinan itself and nalorphine were also employed.

Evidence for the dissociation of morphine effects was noted through the use of certain of the morphine antagonists. This was most notable when the propargyl and the 3'-hydroxypropyl derivatives were employed. Thus, 3-hydroxy-N-propargylmorphinan readily antagonized morphine-induced respiratory depression and N-demethylation without appreciably affecting analgesia, whereas 3-hydroxy-N-3'-hydroxypropylmorphinan was an effective antagonist of analgesia without greatly affecting respiratory depression, or N-demethylation.

3-Hydroxy-N-acetonylmorphinan, a compound not previously reported to possess antimorphine properties, was shown to antagonize both morphine-induced analgesia and respiratory depression and to inhibit microsomal N-demethylation of narcotic drugs.