Further studies of tyrosine surrogates in opioid receptor peptide ligands

A series of opioid peptide ligands containing modified N-terminal tyrosine (Tyr) residues was prepared and evaluated against cloned human μ, δ, and κ opioid receptors. This work extends the recent discovery that (S)-4-carboxamidophenylalanine (Cpa) is an effective tyrosine bioisostere. Amino acids containing negatively charged functional groups in place of tyrosine’s phenolic hydroxyl lacked receptor affinity, while exchange of Tyr for (S)-4-aminophenylalanine was modestly successful. Peptides containing the new amino acids, (S)-4-carboxamido-2,6-dimethylphenylalanine (Cdp) and (S)-β-(2-aminobenzo[d]thiazol-6-yl)alanine (Aba), displayed binding (Ki) and functional (EC50) profiles comparable to the parent ligands at the three receptors. Cdp represents the best performing Tyr surrogate in terms of overall activity, while Cpa and Aba show a subtle proclivity toward the δ receptor.