Synthesis of N alpha-, and C alpha-derivatives of (D)Ala2, Leu5-enkephalin

Some (D)Ala2, Leu5-Enkephalin derivatives containing hydrophilic or hydrophobic moieties have been synthesized by the solution method. Improvement in the analgesic effect was achieved by increasing the hydrophilicity of the parent compound through covalent linkage of the 2-deoxy-D-glucopyranosyl residue to the carboxyl terminal amide nitrogen of leucine 5. Reductive glucosamination of (D)Ala2, Leu5-Enkephalin practically abolishes activity and increase in hydrophobicity lowers the potency of the parent compound in both the in vitro and in vivo tests.