Analogs of the delta opioid receptor selective cyclic peptide. (2-D-penicillamine,5-D-penicillamine)-enkephalin: 2'6'-Dimethyltyrosine and Gly super(3)-Phe super(4) amide bond isostere substitutions

In order to develop systemically-active opioid peptides, the delta -selective, opioid pentapeptide (D-Pen super(2),D-Pen super(5))-enkephalin (DPDPE) was modified by esterification and by substitution of 2',6'-dimethyltyrosine for tyrosine to yield 4. Compound 4 was on the order of 8- and 800-fold more active than DPDPE in both delta and mu opioid radioligand binding assays, respectively, in rat neutral membrane suspensions. Compound 4 was considerably more potent than DPDPE at inhibiting contractions of electrically-stimulated mouse was deferens in vitro, and this effect was very sensitive to naltrindole, a delta -selective opioid antagonist. These observations can be taken as indication that 4 exerts its effect through delta opioid receptors. This interpretation is supported by the finding that the EC sub(50) value of 4 derived in the smooth muscle assay is very similar to that derived in NG108-15 neuroblastoma cells, a preparation devoid of mu receptors.