Dermorphin Gene Sequence Peptide with High Affinity and Selectivity for δ-Opioid Receptors

Skin of the frog Phyllomedusa sauvagei contains a cDNA sequence that codes for the selective μ-receptor peptide dermorphin and a new heptapeptide we have designated as dermorphin gene-associated peptide (DGAP). Investigation of the opioid receptor binding characteristics of synthetic DGAP and [D-Met2]DGAP revealed that the latter peptide had high affinity and selectivity for δ-type opioid receptors in rat brain synaptosomes. The IC50 values for DGAP on μ- and δ-receptors were only 28 µM and 670 nM, respectively, while that for [D-Met2]DGAP was 0.80 nM for δ-receptors and > 1 µM for μ-receptors yielding a very high δ selectivity ratio (SR) of 1345. In comparison, the SR values for [D-Ala2, D-Leu5]enkephalin, [D-Ser2,Leu5,Thr6]enkephalin, and [D-Pen2,5]enkephalin, ligands which are considered to be specific for δ-receptors, were 20, 42, and 301, respectively. Dermorphin, which contains a D-Ala2 residue and is a selective μ-receptor ligand (Lazarus, L.H., Guglietta, A., Wilson, W.E., Irons, B.J., and de Castiglione, R. (1989) J. Biol. Chem. 264, 354–362), exhibits a SR of 0.0055 similar to that for the conventional μ-agonist [D-Ala2,NMePhe4,Gly-ol]enkephalin (0.0040). This finding that frog skin cDNA contains the information to code for dermorphin and DGAP, or the presumed [D-Met2]DGAP molecule, which are among the most selective high affinity opioid ligands described for μ- and δ-receptors, may permit new insight into the design of future opioid receptor agonists and antagonists.