A new family of opioid peptide analogs cyclized through amide bond formation between side-chain amino and carboxyl groups was tested in mu- and delta-opioid receptor selective bio- and binding assays. Within the series of compounds investigated considerable variation in potency and receptor selectivity was observed as a consequence of the introduced conformational restrictions. In particular, the cyclic analogs H-Tyr-D-Glu-Gly-Phe-Lys-NH2 and H-Tyr-D-Glu-Phe-Lys-NH2 showed high preference for mu-receptors over delta-receptors. The development of highly selective receptor ligands constitutes one of the most important prerequisites in efforts aimed at correlating the various types of opioid receptors with specific opioid activities. Recently, the principle of conformational restriction has been successfully applied in the development of selective opioid peptide analogs. In particular, cyclic enkephalin analogs selective for either mu-receptors (1) or delta-receptors (2) have been reported. In the present paper we describe the activity profiles of a new family of side-chain to side-chain cyclized opioid peptide analogs which were obtained through substitution of an alpha, omega-diamino acid and a glutamic or aspartic acid residue in appropriate positions followed by amide bond formation between the side-chain amino and carboxyl groups (cf. Table I). The syntheses of the analogs have been reported elsewhere (3).