Development of a model for the delta-opioid receptor pharmacophore: 3. Comparison of the cyclic tetrapeptide, Tyr-c[D-Cys-Phe-D-Pen]OH with other conformationally constrained delta-receptor selective ligands.

Abstract

We have previously proposed a model of the delta-opioid receptor bound conformation for the cyclic tetrapeptide, Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) based on its conformational analysis and from conformation-affinity relationships observed for its analogues with modified first and third residues. To further verify the model, it is compared here with results of conformational and structure-activity studies for other known conformationally constrained delta-selective ligands: the cyclic pentapeptide agonist, Tyr-c[D-Pen-Gly-Phe-D-Phe]OH (DPDPE): the peptide antagonist, Tyr-Tic-Phe-PheOH (TIPP); the alkaloid agonist, 7-spiroindanyloxymorphone (SIOM); and the related alkaloid antagonist, oxymorphindole (OMI). A candidate delta-bound conformer is identified for DPDPE that provides spatial overlap of the functionally important N-terminal NH3+ and C-terminal COO- groups and the aromatic rings of the Tyr and Phe residues in both cyclic peptides. It is shown that all delta-selective ligands considered have similar arrangements of their pharmacophoric elements, i.e., the tyramine moiety and a second aromatic ring (i.e., the rings of Phe3, Phe4, and Tic2 residues in JOM-13, DPDPE, and TIPP, respectively; the indole ring system in OMI, and the indanyl ring system in SIOM). The second aromatic rings, while occupying similar regions of space throughout the analogues considered, have different orientations in agonists and antagonists, but identical orientations in peptide and alkaloid ligands with the same agonistic or antagonistic properties. These results agree with the previously proposed binding model for JOM-13, are consistent with the view that delta-opioid agonists and antagonists share the same binding site, and support the hypothesis of a similar mode of binding for opioid peptides and alkaloids.