Opioid Activity Profiles of Oversimplified Peptides Lacking in the Protonable N-Terminus

Recently, we described cyclopeptide opioid agonists containing the D-Trp-Phe sequence. To expand the scope of this atypical pharmacophore, we tested the activity profiles of the linear peptides Ac-Xaa-Phe-Yaa (Xaa = L/D-Trp, D-His/Lys/Arg; Yaa = H, GlyNH(2)). Ac-D-Trp-PheNH(2) appeared to be the minimal binding sequence, while Ac-D-Trp-Phe-GlyNH(2) emerged, as the first noncationizable short peptide (partial) agonist with high mu-opioid receptor affinity and selectivity. Conformational analysis suggested that 5 adopts in solution a beta-turn conformation.