Biological activities of cyclic enkephalin pseudopeptides containing thioamides as amide bond replacements

Analogs of H-Tyr-cyclo(Ne-D-Lys-Gly-Phe-Leu) have been prepared which contain thioamides at the 3–4 position (monothio), 3–4 and 5-2 positions (dithio), and 2–3, 3–4, and 5-2 positions (trithio). These compounds have been tested for opioid activity in μ- and δ-receptor selective bio- and binding assays. As the number of sulfurs increased, the biological activities dropped on the guinea pig ileum and fluctuated modestly on the mouse vas deferens assay. Surprisingly, the compounds displayed increasing δ selectivity as the number of sulfurs increased. In the binding assay, the thioamide analogs tended to retain affinity toward the μ receptor. The mono- and dithio-analogs were more μ selective than the parent, while the trithio-analog was more δ selective. These results suggest that the subtle exchange of sulfur for oxygen can have a significant impact on receptor selectivity and affinity, and probably reflect the different conformational/structural requirements for binding vs. the biological transduction event.