TIPP[PSI] - A HIGHLY POTENT AND STABLE PSEUDOPEPTIDE DELTA-OPIOID RECEPTOR ANTAGONIST WITH EXTRAORDINARY DELTA-SELECTIVITY

Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Ticpsi[CH2NH]Phe-Phe-OH (TIPP[psi]) and H-Tyr-Ticpsi-[CH2NH]Phe-OH (TIP[psi]), were tested in mu-, delta-, and kappa-receptor-selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagonist potency in the MVD assay, higher delta receptor affinity and further improved delta receptor selectivity. The more potent compound, TIPP[psi], displayed subnanomolar delta receptor affinity and in direct comparisons with other selective delta ligands was shown to have unprecedented delta specificity (K(i)mu/K(i)delta = 10 500). Furthermore, this compound turned out to be highly stable against enzymatic degradation and, unlike other delta antagonists, showed mu or kappa antagonist properties. TIPP[psi] is likely to find wide use as a pharmacological tool in opioid research.