[D-ALA2]DELTORPHIN-II ANALOGS WITH HIGH-AFFINITY AND SELECTIVITY FOR DELTA-OPIOID RECEPTOR

Nine [D-Ala2]deltorphin II ( DL-II :Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2) analogs having various aliphatic amino acids at positions 5 and 6 were synthesized to gain more information about the role of hydrophobic Val5,6 residues for the δ-opioid receptor selectivity. Binding assays of analogs replaced by Ala demonstrated the importance of hydrophobic Va15,6 residues in DL- II for δ-affinity and selectivity, and especially critical importance of Va15 residue for higher δ-selectivity. By enhancing the hydrophobicity of residues at positions 5 and 6, we have developed analogs with very high δ-affinity and selectivity over those of DL-II, e. g., [Ile5,6], [norleucine5,6] and [γ-methyl-leucine5,6]DL-II, which will be useful as δ-selective ligands for investigation of the physiological role of opioid receptors. © 1991 Academic Press, Inc.