DELTA-OPIOID RECEPTOR-SELECTIVE LIGANDS - DPLPE-DELTORPHIN CHIMERIC PEPTIDE ANALOGS

Further efforts to correlate the topography of the bioactive structure s of DPDPE and the deltorphins, two delta-opioid receptor active pepti de families, are reported. A number of DPLPE-deltorphin chimeric pepti des have been synthesized in which the C-terminal dipeptide delta-addr ess of the deltorphins (-Val-GlyNH(2), -Nle-GlyNH(2)) 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 re sidue in position 5. The radioligand binding assays have revealed a de crease in potency (compared to DPDPE) at delta-receptors when the C-te rminal dipeptides were added to DPDPE. On the other hand, chimeric pep tides of DPLPE with these same C-terminal dipeptides retained high del ta-selectivity and affinity. Similar results were obtained using the m ouse vas deferens (MVD) and guinea pig ileum (GPI) bioassays. The impo rtance of the hydrophilicity of amino acids in positions 2 and 5 for d elta-selectivity is consistent with the previous finding for DPLPE and DPDPE. On the other hand, the replacement of phenylalanine-4 with p-c hlorophenylalanine-4 did not increase delta-selectivity as in DPDPE. T hese findings suggest that the delta-receptor interacts with hybridize d enkephalins and deltorphins somewhat differently than with DPDPE. (C ) Munksgaard 1994.