Deltorphin II analogues with 6-hydroxy-2-aminotetralin-2-carboxylic acid in position 1

Two approaches to the design of very active and highly selective delta opio id peptides were used to obtain new deltorphin analogues with altered hydro phobic and stereoelectronic properties. Deltorphin II analogues were synthe sized with the substitution of Ile instead of Val at positions 5 and 6 in t he address domain and 6-hydroxy-2-aminotetralin-2-carboxylic acid (Hat) ins tead of Tyr(1) in the message domain. In the radioreceptor-binding studies, in which type-specific tritiated opioid ligands were used, (R)- and (S)-Ha t-deltorphins exhibited similar K-i values, revealing high delta selectivit y. The peptides displayed agonist properties in the in vitro bioassay, with IC50 values in the subnanomolar range in the mouse vas deferens assay and in the micromolar or higher range in the guinea pig ileum assay, again demo nstrating a high selectivity toward delta receptors. The agonist property o f the new ligands was confirmed by means of [S-35]- GTP gamma S-binding exp eriments in membranes of the rat frontal cortex.