Synthesis and biological activity of branched enkephalin analogues

Article abstract of DOI:10.1016/S0223-5234(98)80060-3

The synthesis and biological activity of a new type of enkephalin analogs are reported. A series of branched pentapeptides of the enkephalin sequence with replacement of 2-glycine by D-ornithine and branching of the peptide chain in position 2 by attachment of proline, leucine, asparagine or methionine residues to the 8-amino group of D-ornithine were synthesized by classical solution methodology. Analgesic activity of the new analogs was assayed by the 'tail pinch' method following intracisternal and intravenous administrations to mice. They showed higher analgesic potency and longer duration of action as compared to linear and cyclic pentapeptides with the same amino acid composition. The activity determined in the GPI and MVD bioassays, and in a binding assay, revealed the preference of the branched analogs for the μ-type of opioid receptor over the δ-type. These results raise the possibility to synthesize enkephalin analogs with high analgesic potency and opiate receptor selectivity by varying the chemical character and length of the side chain in the 2-position.