Synthesis and in vitro evaluation of lipoamino acid and carbohydrate-modified enkephalins as potential antinociceptive agents

The principal hindrance to drug uptake into central nervous tissue is the blood-brain barrier (BBB). In addition, potential peptide-based neuropharmaceuticals are rapidly destroyed by intra-and extracellular peptidases. In an attempt to address these biological hurdles, a series of lipo-, glyco- and glycolipo-conjugates of Leu-enkephalin have been synthesised via novel solid-phase strategies, and their in vitro activity assessed using mouse vas deferens (MVD) and guinea pig ileum (GPI) assays. Conjugation of a single lipoamino acid onto the C-terminal of the Leu-enkephalin molecule retains biological activity whilst increasing the molecule's overall lipophilicity. Conjugation of a glucuronic acid analogue in an analogous position, however, increases activity 40-fold when compared to the native peptide and induces a high degree of delta-opioid receptor selectivity. (C) 1998 Elsevier Science B.V.