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 (K_i) 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.