of Work: Molecular modeling comprised of molecular dynamics, conformational searching and superimpositions with crystal structures were used to propose a delta-opioid antagonist pharmacophore and to assess the tertiary structure of the delta opioid agonist deltorphin and the delta antagonist containing the Dmt-Tic pharmacophore. A study on [Leu]deltorphin C was undertaken in order to determined if a structural change occurred that could substantiate differences in activity. Conformational changes were examined by 1-H NMR (COSY, NOESY, HOHAHA, ROESY, DQF-COSY experiments)and CD under variying solvent and temperature conditions in Japan. The aromatic ring distance may be a singularly important characteristic of delta antagonists to provide a """"""""receptor-bound conformation"""""""" in spite of the inherent flexibility of the peptide. The topographical features observed with the Dmt-Tic pharmacophore differentiate it from all other peptides, however, it coincides with that of cyclo(Dmt-Tic) and the X-ray diffraction data on N,N(Me)2-Dmt-Tic-OH, but not H-Dmt-Tic-NH-1-adamantane whose aromatic rings splay outward. The data suggest that the presumed receptor-bound conformation involves a sandwich arrangement betweent the Dmt and Tic aromatic rings. Thus, intraring distance of delta-opioid antagonists may portend biological differences. Small peptide analogues with dual receptor binding characteristics or selectivity for the mu opioid receptor equally assist in applying molecular modeling in a predictive mode. Thus, our delta- and mu-opioid antagonist and agonist pharmacophores will serve as scaffolds to assit in the design of new potent ligands.
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