Modification of the Phe 3 aromatic moiety in delta receptor‐selective dermorphin/deltorphin‐related tetrapeptides Effects on opioid receptor binding

The previously described cyclic delta opioid receptor‐selective tetrapeptide H‐Tyr‐ d ‐Cys‐Phe‐ d ‐Pen‐OH (JOM‐13) was modified at residue 3 by incorporation of both natural and unnatural amino acids with varying steric, electronic, and lipophilic properties. Effects on mu and delta opioid receptor binding affinities were evaluated by testing the compounds for displacement of radiolabeled receptor‐selective ligands in a guinea pig brain receptor binding assay. Results obtained with the bulky aromatic 1‐Nal 3 and 2‐Nal 3 substitutions suggest that the shape of the receptor subsite with which the side chain of the internal aromatic residue interacts differs for delta and mu receptors. This subsite of either receptor can accommodate the transverse steric bulk of the 1‐Nal 3 side chain but only the delta receptor can readily accept the more elongated 2‐Nal 3 side chain. Several analogs with pi‐excessive heteroaromatic side chains in residue 3 were examined. In general, these analogs display diminished binding to mu and delta receptors, consistent with previous findings for analogs with residue 3 substitutions of modified electronic character. Several analogs with alkyl side chains in residue 3 were also examined. While delta receptor binding affinity is severely diminished with Val 3 , Ile 3 , and Leu 3 substitutions, Cha 3 substitution is very well tolerated, indicating that, contrary to the widely held belief, an aromatic side chain in this portion of the ligand is not required for delta receptor binding. Where possible, comparison of results in this delta‐selective tetrapeptide series with those reported for analogous modification in the cyclic delta‐selective pentapeptide [ d ‐Pen 2 , d ‐Pen 5 ]enkephalin (DPDPE) and linear pentapeptide enkephalins reveals similar trends.