Molecular modeling (molecular dynamics, conformational searching, Monte Carlo) and use of data on the crystalized structure of bovine rhodopsin (excluding the intracellular and extracellular sequences) was used to propose a model of the delta-opioid receptor. Specific residues existing in the delta receptor were exchanged in that 7-transmembrane protein. A variety of agonist and antagonist pharmacophores were then assessed to determine if the binding pocket delineated by the minimized molecular model fit the ligands and refelcted their known biological activities and receptor affinities. Conformational changes in the peptides first first examined by 1-H NMR (COSY, NOESY, HOHAHA, ROESY, DQF-COSY experiments), CD under variying solvent and temperature conditions in Japan, and crystalized peptides when available. The aromatic ring distance may be a singularly important characteristic of delta antagonists and agonists providing a "receptor-bound conformation" in spite of the inherent flexibility of the peptide. The mu agonists exhiibted a poor fit in the delta receptor pocket region. The topographical features observed with the Dmt-Tic pharmacophore differentiate it from all other peptides and its interaction with side-chains in the receptor pit. The data suggest that the presumed receptor-bound conformation of the peptide ligand and receptor involves stacking between aromatic rings and hydrogen bonding and mu agonists poorly interacted with those residues specific for delta ligands. Thus, intra-ring distance of delta-opioid antagonists may portend biological differences. Peptide analogues with dual receptor binding characteristics or selectivity for the mu opioid receptor equally assist in using molecular modeling in a predictive mode. Thus, model of the delta receptor and our delta- and mu-opioid antagonist and agonist pharmacophores will serve as scaffolds in the design of new potent ligands.