Using the μ-receptor selective cyclic enkephalin analog Tyr-cyclo[-N ε-D-Lys-Gly-Phe-Leu-] as parent compound, a series of analogs with substitutions in positions 1, 4 and 5 were synthesized and their potencies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assay were compared with those of correspondingly modified linear enkephalins. Structure-activity relationships observed with cyclic compounds did not always parallel those determined with linear analogs. Most strikingly, substitution of phenylalanine for tyrosine in position 1 of the cyclic analog resulted in a compound showing twice the potency of [Leu 5]enkephalin in the GPI-assay. The effect of the latter compound is fully naloxone-reversible and it represents the first example of a potent opioid peptide lacking an intact tyrosyl residue at the N-terminal.