Evidence of a peptide backbone contribution toward selective receptor recognition for leucine enkephalin thioamide analogs

Abstract

The in vitro opioid activities of a series of leucine enkephalin analogs containing a thioamide linkage in place of the peptide bond at various positions of the backbone were determined in μ- and δ-receptor-selective bio- and binding-assays. Thioamide substitution in the 1–2 position resulted in an inactive compound, whereas the same modification in the 2–3 and 4–5 position produced potency enhancement. Most interestingly, the 2–3 modified analog showed a 3 to 5 times higher preference for δ- over μ-receptors than natural leucine enkephalin. These results suggest that subtle backbone modifications can have a profound effect on receptor affinity and selectivity of biologically active peptides.