Synthesis and Biological Activities of Cyclic Lanthionine Enkephalin Analogues:  δ-Opioid Receptor Selective Ligands (original) (raw)

The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[D-Ala L-Gly-Phe-D-Ala L ]-OH (1a), Tyr-c[D-Val L-Gly-Phe-D-Ala L ]-OH (1b), Tyr-c[D-Ala L-Gly-Phe-Ala L ]-OH (1c), and Tyr-c[D-Val L-Gly-Phe-Ala L ]-OH (1d), where Ala L and Val L denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against µ-, δ-, and κ-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as D-Val L in position 2, show substantial selectivity toward the δ-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as D-Ala L in position 2, bind to both µ-and δ-opioid receptors. The in vivo thermal escape assay by intrathecal administration showed that the analogues 1b and 1d are among the most potent ligands at producing antinociception through the δ-opioid receptor. The picomolar potencies of analogues 1a and 1c in the intrathecal (it.) assay strongly indicate that µ-and δ-opioid receptors interact synergistically to modulate the antinociceptive responses.