Synthesis and biological evaluation of constrained analogues of the opioid peptide H-Tyr-D-Ala-Phe-Gly-NH₂ using the 4-amino-2-benzazepin-3-one scaffold

Abstract

The synthesis of conformationally restricted dipeptidic moieties 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba)-Gly ([(4S)-amino-3-oxo-1,2,4,5-tetrahydro-1H-2-benzazepin-2-yl]-acetic acid) and 8-hydroxy-4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Hba)-d-Ala ([(4S)-amino-8-hydroxy-3-oxo-1,2,4,5-tetrahydro-benzo[c]azepin-2-yl]-propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N-acyliminium precursor. Introducing these Aba scaffolds into the N-terminal tetrapeptide of dermorphin (H-Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH₂)-induced remarkable shifts in affinity and selectivity towards the opioid μ- and δ-receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N-terminal tetrapeptide H-Tyr-d-Ala-Phe-Gly-NH₂, which is the minimal subunit of dermorphin needed for dermorphin-like opiate activity.