Abstract

Our postulate that opiate agonist and antagonist action is determined by the difference in the physicochemical properties between agonist-receptor complex and the complex formed with antagonist was tested using cerebroside sulfate as a model receptor. All of the drugs examined induced the [³H]cerebroside sulfate transfer from an aqueous phase to a nonaqueous phase. However, most of the agonists were more effective in inducing the transfer than most relatively pure antagonists and in a series of homologues, the maximum transfer induced by the agonists was larger than that induced by the antagonists. Moreover, the transfer induced by levorphanol was reversed by various opiate antagonists, but not by agonists. Both the transfer induced by the drugs used and the inhibition by various types of opiate antagonists correlated closely with their analgetic potencies in man and their antagonisms of the agonist effects in the isolated guinea pig ileum, respectively. Partial agonists and antagonists exhibited biphasic effects; at the low concentration, they antagonized the agonist-induced [³H]cerebroside sulfate transfer but at the higher concentration they induced their own transfer. When the [³H]cerebroside sulfate transfer induced by agonists and the inhibition by antagonists were compared to that induced by inorganic cations, the tightness of the ionic interaction between the cationic nitrogen atom of the drug and the anionic sulfate group of CS could serve to explain the agonist efficacy, while hydration of the ionic bond determines the antagonist efficacy. Based on the molecular mechanism of opiate-cerebroside sulfate interaction, an opiate receptor theory was proposed.