Dermorphin and deltorphin heptapeptide analogues: replacement of Phe residue by Dmp greatly improves opioid receptor affinity and selectivity

The usefulness of 2,6-dimethylphenylalanine (Dmp) as a Phe surrogate in two opioid peptides, dermorphin (DM) and deltorphin II (DT), was investigated. Compared to DM, [ -Dmp3]DM (1) showed a 170-fold increase in μ affinity and only a 4-fold increase in δ affinity, resulting in a 40-fold improvement in μ receptor selectivity. Compared to DT, [ -Dmp3]DT (3) showed a 22-fold increase in δ affinity and somewhat of a loss in μ affinity, and consequently a marked (75-fold) improvement in δ receptor selectivity. The -Dmp replacement, however, resulted in a great loss in receptor selectivity in each of the peptides. The specific receptor interactions of 1 and 3 were confirmed by in vitro bioassays. Analogues 1 and 3 seem to be useful as pharmacological tools for the study of opioid systems.