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

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Abstract
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-AlaL-Gly-Phe-d-AlaL]-OH (1a), Tyr-c[d-ValL-Gly-Phe-d-AlaL]-OH (1b), Tyr-c[d-AlaL-Gly-Phe-AlaL]-OH (1c), and Tyr-c[d-ValL-Gly-Phe-AlaL]-OH (1d), where AlaL and ValL 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-ValL in position 2, show substantial selectivity toward the δ-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as d-AlaL 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.