Opioid antagonist properties of the highly delta-receptor-selective BOC-Tyr-Pro-Gly-Phe-Leu-Thr (OtBu) peptide and of its Phe1 and Mel1 analogues

BOC-Tyr-Pro-Gly-Phe-Leu-Thr(OtBu) is a potent, highly delta-opioid receptor-selective competitive antagonist, the Ke values in the mouse vas deferens in vitro assay against [D-Ala2, D-Leu5]-enkephalin [D-Pen2, D-Pen5]enkephalin and deltorphin-II being 39.5, 38.7 and 27.3 nM, respectively, whereas those against [D-Ala2, MePhe4-Gly5-ol]enkephalin (DAMGO) and ethylketocyclazocine in the guinea-pig ileum are 368,000 and > 200,000 nM, giving a higher than 9000-fold delta- vs mu- and a higher than 5000-fold delta- vs kappa-selectivity ratio. The Ki values against various labeled delta-ligands in the rat brain receptor binding assay were in the 300-1000 nM range, whereas the Ki against [3H]-DAMGO was higher than 30,000 nM. The striking discrepancies between bioassay and receptor binding data show another aspect of already recognized differences of mouse vas deferens and rat brain delta-receptors. With the aim of producing a delta-selective affinity ligand, we synthesized the BOC-Mel1 derivative; however, there was a 175-fold loss of delta-receptor affinity in the bioassay and no indication of an irreversible interaction, but a delta-agonist effect appeared in spite of nonprotonated nitrogen. The corresponding BOC-Phe1 derivative had a 10 times higher affinity and, apparently, no agonist activity.