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Enkephalin analogs containing 4,4‐difluoro‐2‐aminobutyric acid: Synthesis and fluorine effect on the biological activity
Author(s) -
Winkler Dirk,
Sewald Norbert,
Burger Klaus,
Chung Nga N.,
Schiller Peter W.
Publication year - 1998
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(199812)4:8<496::aid-psc170>3.0.co;2-8
Subject(s) - aminobutyric acid , chemistry , enkephalin , fluorine , biological activity , stereochemistry , pharmacology , leu enkephalin , combinatorial chemistry , organic chemistry , biochemistry , medicine , in vitro , opioid , receptor
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 μ and δ 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 δ agonist potency than d ‐amino acid substitution, [ d ‐DFAB 3 ]DPDPE turned out to be a more potent δ agonist than [ l ‐DFAB 3 ]DPDPE. Furthermore, [ d ‐DFAB 3 ]DPDPE showed over 100‐fold higher δ agonist potency than [ d ‐Abu 3 ]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.