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

✍ Scribed by Dirk Winkler; Norbert Sewald; Klaus Burger; Nga N. Chung; Peter W. Schiller

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 92 KB
• Volume: 4
• Category: Article
• ISSN: 1075-2617
• DOI: 10.1002/(sici)1099-1387(199812)4:8<496::aid-psc170>3.0.co;2-8

✦ Synopsis

Analogs of Met-enkephalin and [D-Pen 2 , D-Pen 5 ]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-DFAB 2 , Met 5 -NH 2 ]enkephalin showed v and l agonist potencies comparable to those of natural [Leu 5 ]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 l agonist potency than D-amino acid substitution, [D-DFAB 3 ]DPDPE turned out to be a more potent l agonist than [L-DFAB 3 ]DPDPE. Furthermore, [D-DFAB 3 ]DPDPE showed over 100-fold higher l agonist potency than [D-Abu 3 ]DPDPE (Abu = 2-aminobutyric acid), indicating that the fluorine substituents interact favorably with a l opioid receptor subsite.