2′,6′-Dimethylphenylalanine (Dmp) Can Mimic the N-Terminal Tyr in Opioid Peptides

Substitution of 2′,6′-dimethyltyrosine (Dmt) for the N-terminal Tyr in opioid peptides has recently been shown to be a promising tool for improving opioid receptor affinity and biological activity. We have also demonstrated that another unnatural amino acid, 2′,6′-dimethylphenylalanine (Dmp), is not only an excellent substitute for Phe at position 3 but also can mimic the aromatic N-terminal Tyr residue in a μ opioid receptor-selective dermorphin analogue (YRFB: Tyr-D-Arg-Phe-βAla-NH2). To further evaluate the value of Dmp in opioid peptides, we investigated Dmp1-substituted analogues of the δ receptor ligands, deltorphin II (DLT: Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2) and enkephalin (ENK: Tyr-Gly-Gly-Phe-Leu). In the receptor binding assay, both [Dmp1]DLT and [Dmp1]ENK bound to the δ-receptor with high affinity and selectivity, and were nearly as effective as the parent peptides. The potency of the Dmp1-peptides on the MVD and GPI assays correlated well with the receptor binding affinity data. These results are in contrast to the tendency of corresponding Dmt1-analogues to have poor receptor selectivity. Taken together with the results with YRFB, we conclude that the Dmp1-peptide is superior to the corresponding Dmt1-peptide in its receptor selectivity. [Dmp1]DLT and [Dmp1]YRFB may serve as pharmacological tools for the studies of ligand recognition and opioid receptor signal transduction.