Synthesis and Biological Evaluation of a Metazocine-Containing Enkephalinamide. Evidence for Nonidentical Roles of the Tyramine Moiety in Opiates and Opioid Peptides

In an effort to test the hypothesis that the tyramine moiety present in opiates and in opioid peptides plays an identical functional role at opioid receptors, a hybrid enkephalinamide (3) that contains (−)-metazocine (4a) in place of Tyr¹ was synthesized. It was found that 3 and its congeners are inactive or feebly active in the electrically stimulated guinea pig ileum and mouse vas deferens preparations. The results of these studies suggest that the tyramine moiety in opiates and related structures does not play the same functional role as that in the opioid peptides. It is suggested that the different functional roles of the tyramine moiety in opiates and opioid peptides is a consequence of different modes of interaction with common receptors.