DEVELOPMENT OF A MODEL FOR THE DELTA-OPIOID RECEPTOR PHARMACOPHORE .3. COMPARISON OF THE CYCLIC TETRAPEPTIDE, TYR-C[D-CYS-PHE-D-PEN]OH WITHOTHER CONFORMATIONALLY CONSTRAINED DELTA-RECEPTOR SELECTIVE LIGANDS

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(JO M-13) based on its conformational analysis and from conformation-affin ity relationships observed for its analogues with modified first and t hird residues. To further verify the model, its is compared here with results of conformational and structure-activity studies for other kno wn conformationally constrained delta-selective ligands: the cyclic pe ntapeptide agonist, Tyr-c[D-Pen-Gly-Phe-D-Phe]OH (DPDPE); the peptide antagonist, Tyr-Tic-Phe-PheOH (TIPP); the alkaloid agonist, 7-spiroind anyloxymorphone (SIOM); and the related alkaloid antagonist, oxymorphi ndole (OMI). A candidate delta-bound conformer is identified for DPDPE that provides spatial overlap of the functionally important N-termina l NH3+ and C-terminal COO- groups and the aromatic rings of the Tyr an d Phe residues in both cyclic peptides. It is shown that all delta-sel ective ligands considered have similar arrangements of their pharmacop horic elements, i.e., the tyramine moiety and a second aromatic ring ( i.e., the rings of Phe(3), Phe(4), and Tic(2) residues in JOM-13, DPDP E, and TIPP, respectively; the indole ring system in OMI, and the inda nyl ring system in SIOM). The second aromatic rings, while occupying s imilar regions of space throughout the analogues considered, have diff erent orientations in agonists and antagonists, but identical orientat ions in peptide and alkaloid ligands with the same agonist or antagoni stic properties. These results agree with the previously proposed bind ing model for JOM-13, are consistent with the view that delta-opioid a gonists and antagonists share the same binding site, and support the h ypothesis of a similar mode of binding for opioid peptides and alkaloi ds. (C) John Wiley & Sons, Inc.