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. The study on deltorphins were conducted in order to induce structural changes in peptides in which unsual amino acids are substituted for their natural cognate, such as Aib and or aminocycloalkanes, to limit their inherent flexibility. Conformational changes were detected by 1-H NMR (using COSY, NOESY, HOHAHA, ROESY, DQF-COSY experiments) and CD under variying solvent and temperature conditions. The aromatic ring distance may be an important characteristic of delta antagonists to provide a receptor-bound conformation. The 3-D structure of H-Dmt-Tic- OH contains a cis peptide bond, gauche+ orientation of the Tic side chain, a near parallel orientation and close proximity of 5.4 A between the aromatic rings. The topographical features observed with the Dmt- Tic pharmacophore differentiate if from all other peptides. The data suggest that the presumed receptor-bound conformation involves a sandwich arrangement betweent the Dmt and Tic aromatic rings. This was confirmed by X-ray diffraction analyese on N,N(dimethyl)Dmt-Tic-OH. In fact, the small intraring distance of delta-opioid antagonists differs from the extended intramolecular distances of aromatic rings (11-12 A) found for delta, and mu antagonists as well as mu agonists. Molecular modeling continues to delineate differences between delta and mu antagonists and how their structure is compatible with proposed receptor binding sites. Small peptide analogues with dual receptor binding characteristics or selectivity for the mu opioid receptor will assist in applying molecular modeling in a predictive mode. In fact, analysis of a new opioid agonist with a weak delta antagonist activity suggests that the concept of message and address domains must be modified: the linear sequence of the peptide may not be the correct determinant to verify the amino acid residue side chains involved in these recognition sites. Thus, our delta- and mu-opioid antagonist and agonist pharmacophores will serve as scaffolds to design new potent ligands. - Molecular modeling; molecular dynamics; Monte Carlo; conformational searching; low energy conformers; petptide structure.

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Balboni, Gianfranco; Onnis, Valentina; Congiu, Cenzo et al. (2007) Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore. Bioorg Med Chem 15:3143-51
Li, Tingyou; Jinsmaa, Yunden; Nedachi, Masahiro et al. (2007) Transformation of mu-opioid receptor agonists into biologically potent mu-opioid receptor antagonists. Bioorg Med Chem 15:1237-51
Li, Tingyou; Shiotani, Kimitaka; Miyazaki, Anna et al. (2007) Bifunctional [2',6'-dimethyl-L-tyrosine1]endomorphin-2 analogues substituted at position 3 with alkylated phenylalanine derivatives yield potent mixed mu-agonist/delta-antagonist and dual mu-agonist/delta-agonist opioid ligands. J Med Chem 50:2753-66
Marczak, Ewa D; Jinsmaa, Yunden; Li, Tingyou et al. (2007) [N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties. J Pharmacol Exp Ther 323:374-80
Vazquez, M Eugenio; Blanco, Juan B; Salvadori, Severo et al. (2006) 6-N,N-dimethylamino-2,3-naphthalimide: a new environment-sensitive fluorescent probe in delta- and mu-selective opioid peptides. J Med Chem 49:3653-8
Li, Tingyou; Tsuda, Yuko; Minoura, Katsuhiko et al. (2006) Enantioselective synthesis of a phenylalanine library containing alkyl groups on the aromatic moiety: confirmation of stereostructure by x-ray analysis. Chem Pharm Bull (Tokyo) 54:873-7
Jinsmaa, Yunden; Marczak, Ewa; Fujita, Yoshio et al. (2006) Potent in vivo antinociception and opioid receptor preference of the novel analogue [Dmt1]endomorphin-1. Pharmacol Biochem Behav 84:252-8
Miyazaki, Anna; Fujisawa, Yutaka; Shiotani, Kimitaka et al. (2005) Studies on the mechanism of 1,2-dihydropyrazin-2-one ring formation from dipeptidyl chloromethyl ketone and its chemical properties: immediate deamination during catalytic hydrogenation. Chem Pharm Bull (Tokyo) 53:1152-8
Li, Tingyou; Fujita, Yoshio; Shiotani, Kimitaka et al. (2005) Potent Dmt-Tic pharmacophoric delta- and mu-opioid receptor antagonists. J Med Chem 48:8035-44
Balboni, Gianfranco; Guerrini, Remo; Salvadori, Severo et al. (2005) Conversion of the potent delta-opioid agonist H-Dmt-Tic-NH-CH(2)-bid into delta-opioid antagonists by N(1)-benzimidazole alkylation(1). J Med Chem 48:8112-4

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