Delta opioid receptor selective ligands; DPLPE-deltorphin chimeric peptide analogues.

Further efforts to correlate the topography of the bioactive structures of DPDPE and the deltorphins, two delta-opioid receptor active peptide families, are reported. A number of DPLPE-deltorphin chimeric peptides have been synthesized in which the C-terminal dipeptide delta-address of the deltorphins (-Val-GlyNH2, -Nle-GlyNH2) have been linked to the highly delta-opioid selective cyclic peptides DPDPE or DPLPE. These studies demonstrate that a major structural feature determining high potency of hybrid analogues is the chirality of the amino acid residue in position 5. The radioligand binding assays have revealed a decrease in potency (compared to DPDPE) at delta-receptors when the C-terminal dipeptides were added to DPDPE. On the other hand, chimeric peptides of DPLPE with these same C-terminal dipeptides retained high delta-selectivity and affinity. Similar results were obtained using the mouse vas deferens (MVD) and guinea pig ileum (GPI) bioassays. The importance of the hydrophilicity of amino acids in positions 2 and 5 for delta-selectivity is consistent with the previous finding for DPLPE and DPDPE. On the other hand, the replacement of phenylalanine-4 with p-chlorophenylalanine-4 did not increase delta-selectivity as in DPDPE. These findings suggest that the delta-receptor interacts with hybridized enkephalins and deltorphins somewhat differently than with DPDPE.