h-tyrosyl-cyclo(cysteinyl-phenylalanyl-penicillaminyl)-oh and 7-spiroindanyloxymorphone

Based upon the message-address concept, this molecular modeling study used the delta-selective agonist spiroindanyloxymorphone (SIOM) as a molecular template for a conformational search and analysis of delta-selective opioid peptides. It was assumed that the tyramine moiety plays the same role for delta-opioid receptor recognition in both peptide and non-peptide ligands. Using 20 reported low-energy conformations of Tyr-cyclo[D-Cys-D-Pen]-OH (JOM-13) for comparison, the geometrical relationship of the two aromatic rings present in SIOM was used for the identification of potential active conformations of JOM-13, from which two delta-receptor-binding models (I and II) were constructed. Models I and II differ from each other in the arrangement of the peptide backbones. To evaluate the two models, a conformational search of two other known delta-selective ligands, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Pen2,L-Pen5]enkephalin (DPLPE) was performed, using the geometrical relationship of the two aromatic rings defined in the two receptor-binding models as a molecular template. Among the conformations generated from the molecular simulation, low-energy conformers of DPDPE and DPLPE conforming to models I and II were identified. Unlike model I, conformers of DPDPE and DPLPE that fit model II contain a cis amide bond in the Gly3 residue.

Topics: Drug Design; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Naltrexone; Narcotic Antagonists; Oxymorphone; Peptides, Cyclic; Protein Binding; Protein Conformation; Receptors, Opioid, delta; Spiro Compounds; Structure-Activity Relationship