In order to develop systemically-active opioid peptidea, the &selective, opioid pentapeptide [~-Pen*,~-Pen~]-enkephalin (DPDPE) was modified by eaterification and by substitution of 2', 6'-dimethyltyrosine for tyrosine to yield 4. Compound 4 was on the order of 8-and 800-fold more active than DPDPE in both 6 and p opioid radioligand binding assays, respectively, in rat neural membrane suspensions. Compound 4 was considerably more potent than ...