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 comp ounds, H-Tyr-Ticpsi[CH2NH]Phe-Phe-OH (TIPP[psi]) and H-Tyr-Ticpsi-[CH2 NH]Phe-OH (TIP[psi]), were tested in mu-, delta-, and kappa-receptor-s elective binding assays and in the guinea pig ileum (GPI) and mouse va s deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagon ist potency in the MVD assay, higher delta receptor affinity and furth er improved delta receptor selectivity. The more potent compound, TIPP [psi], displayed subnanomolar delta receptor affinity and in direct co mparisons with other selective delta ligands was shown to have unprece dented delta specificity (K(i)mu/K(i)delta = 10 500). Furthermore, thi s compound turned out to be highly stable against enzymatic degradatio n and, unlike other delta antagonists, showed mu or kappa antagonist p roperties. TIPP[psi] is likely to find wide use as a pharmacological t ool in opioid research.