Enkephalin analogs containing 4,4-difluoro-2-aminobutyric acid: Synthesis and fluorine effect on the biological activity

Analogs of Met-enkephalin and d -Pen², d -Pen⁵]enkephalin (DPDPE) containing the partially fluorinated amino acid 4,4-difluoro-2-aminobutyric acid (DFAB) in the 2- or 3-position of the peptide sequence were synthesized and their opioid activities and receptor selectivities were determined in vitro. The linear fluorinated d -DFAB², Met⁵-NH₂]enkephalin showed μ and δ agonist potencies comparable to those of natural Leu⁵]enkephalin. The partially fluorinated DPDPE analogs behaved differently as compared with their non-fluorinated correlates. While l -amino acid substitution in position 3 of DPDPE usually resulted in higher δ agonist potency than d -amino acid substitution, d -DFAB³]DPDPE turned out to be a more potent δ agonist than l -DFAB³]DPDPE. Furthermore, d -DFAB³]DPDPE showed over 100-fold higher δ agonist potency than d -Abu³]DPDPE (Abu=2-aminobutyric acid), indicating that the fluorine substituents interact favorably with a δ opioid receptor subsite. © 1998 European Peptide Society and John Wiley & Sons, Ltd.