THE IMPORTANCE OF STERIC CONFIGURATION IN CERTAIN MORPHINEMIMETIC ACTIONS OF SYNTHETIC ANALGETICS

¹ Department of Pharmacology, University of California Medical Center, San Francisco, California

Mice were injected intraventricularly with the levorotatory, dextrorotatory, and racemic forms of -acetylmethadol, methadone and 3-hydroxy-N-methylmorphinan, and the "analgetic" and toxic effects determined.

It was found that two kinds of effect in depressing the tail-flick response to a thermal stimulus could be distinguished. One effect, designated as a morphinemimetic response, was obtained with d--acetylmethadol, l-methadone, and levorphanol; the effect required very low doses (between 10 to 30 µg/kg) and was antagonized by pretreatment with nalorphine. The other effect was not influenced by nalorphine and was obtained with high doses (1 to 2.5 mg/kg) of all optical forms of -acetylmethadol and methadone. Possible sites of action for the two different responses are discussed. It was concluded that the morphinemimetic response is highly dependent on spatial configuration and that the second kind of effect, while showing less steric discrimination, was not wholly a nonspecific action since it could not be elicited by the more rigidly structured hydroxy-N-methyl-morphinan.

The toxic actions of these compounds show no configurational discrimination. The evidence supporting this conclusion includes the observations that (a) except for -acetylmethadol the same dosage levels were required for all three isomeric forms; (b) in all cases nalorphine pretreatment was ineffective; and (c) the same signs and symptoms were seen with all compounds.

l--Acetylmethadol was selected for further study of analgetic effects by the hot-plate method. When this compound was injected subcutaneously in mice in doses near the ED50 (3.25 mg/kg) it produced "analgesia" after a delayed onset. Raising the dose to the calculated ED90 (21 mg/kg) resulted in an immediate prolongation of the hot-plate reaction time, which lasted at least 6 hours. The intensity of the "analgetic" response was significantly reduced by pretreatment with nalorphine or with the metabolic inhibitor, SKF 525A, suggesting that the effects of l--acetylmethadol after subcutaneous administration are due, not to the unmetabolized drug, but to a biotransformation product with morphinemimetic properties.