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

Abstract

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 mu and delta 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 delta agonist potency than D-amino acid substitution. [D-DFAB3]DPDPE turned out to be a more potent delta agonist than [L-DFAB3]DPDPE. Furthermore, [D-DFAB3]DPDPE showed over 100-fold higher delta agonist potency than [D-Abu3]DPDPE (Abu = 2-aminobutyric acid), indicating that the fluorine substituents interact favorably with a delta opioid receptor subsite.