Biological activities of cyclic enkephalin pseudopeptides containing thioamides as amide bond replacements.
Analogs of H-Tyr-cyclo(N epsilon-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 mu- and delta-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 delta selectivity as the number of sulfurs increased. In the binding assay, the thioamide analogs tended to retain affinity toward the mu receptor. The mono- and dithio-analogs were more mu selective than the parent, while the trithio-analog was more delta 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 conformation/structural requirements for binding vs. the biological transduction event.
Sherman
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DB
Department of Chemistry, University of Louisville, KY 40292.
Spatola
A F
AF
Wire
W S
WS
Burks
T F
TF
Nguyen
T M
TM
Schiller
P W
PW
D000577:Amides; D001681:Biological Assay; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis; D010456:Peptides, Cyclic; D013329:Structure-Activity Relationship; D013854:Thioamides
D000577:Amides; D010456:Peptides, Cyclic; D013854:Thioamides; D004743:Enkephalin, Leucine