Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208

An alanine scan was performed on the novel κopioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent invivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid-phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay invivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μopioid receptors (MOR). Thus analogues 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity invivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics.