Synthesis, pharmacological evaluation and conformational investigation of endomorphin-2 hybrid analogues

This study reports on new pharmacologically active endomorphin-2 analogues, incorporatingβ2-hPhe,β3- hPhe and β3-hTic unnatural amino acids in the place of the Phe3–Phe4residues. Such α, β-hybrid analogues were designed to exploit the great potential of β-amino acids in generating conformational variation at the key positions 3 and 4, with the aim of evaluating the effect on the opioid binding affinity. Ligand-stimulated binding assays indicated that some analogues retained a significant affinity, especially for the δ receptor. 1H NMR and molecular modelling suggested the predominance of bent structures for all compounds. The molecular docking with the μ-opioid receptor model was also performed, highlighting a common binding mode for active compounds and helping to rationalize the observed structure–activity data.