Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity.

Abstract

The design and synthesis of leu-enkephalin analogs by replacing the glycine residues with N-(2-thioethyl)glycines and opening the cyclisation potential is presented. The cyclization (stapling) was achieved using bifunctional reagents (hexafluorobenzene and trithiocyanuric acid derivatives). The CD conformational studies of the stapled analogs suggest that the peptides adopt the type I β-turn conformation, which is in agreement with the theoretical analysis. The analog containing a trithiocyanuric acid derivative with a benzyl substituent shows potent analgesic activity.