OPIOID ANTAGONIST PROPERTIES OF THE HIGHLY 6-RECEPTOR-SELECTIVE BOC-TYR-PRO-GLY-PHE-LEU-THR(O(T)BU) PEPTIDE AND OF ITS PHE(1) AND MEL(1) ANALOGS

BOC-Tyr-Pro-Gly-Phe-Leu-Thr(O(t)Bu) is a potent, highly delta-opioid r eceptor-selective competitive antagonist, the K-e values in the mouse vas deferens in vitro assay against [D-Ala(2), D-Leu(5)]enkephalin, [D -Pen(2), D-Pen(5)]enkephalin and deltorphin-II being 39.5, 38.7 and 27 .3 nM, respectively, whereas those against [D-Ala(2), MePhe(4)-Gly(5)- ol]enkephalin (DAMGO) and ethylketocyclazocine in the guinea-pig ileum are 368,000 and > 200,000 nM, giving a higher than 9000-fold delta- v s mu- and a higher than 5000-fold delta- vs kappa-selectivity ratio. T he K-i values against various labeled delta-ligands in the rat brain r eceptor binding assay were in the 300-1000 nM range, whereas the K-i a gainst [H-3]-DAMGO was higher than 30,000 nM. The striking discrepanci es between bioassay and receptor binding data show another aspect of a lready recognized differences of mouse vas deferens and rat brain delt a-receptors. With the aim of producing a delta-selective affinity liga nd, we synthesized the BOC-Mel(1) derivative; however, there was a 175 -fold loss of delta-receptor affinity in the bioassay and no indicatio n of an irreversible interaction, but a delta-agonist effect appeared in spite of nonprotonated nitrogen. The corresponding BOC-Phe(1) deriv ative had a 10 times higher affinity and, apparently, no agonist activ ity.