Comparison of cyclic delta-opioid peptides with non-peptide delta-agonist spiroindanyloxymorphone (SIOM) using the message-address concept: a molecular modeling study.
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.
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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
D015195:Drug Design; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000378:metabolism; D010111:Oxymorphone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004745:Enkephalins; D008024:Ligands; D009292:Narcotic Antagonists; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D013141:Spiro Compounds; C070386:H-tyrosyl-cyclo(cysteinyl-phenylalanyl-penicillaminyl)-OH; C082822:7-spiroindanyloxymorphone; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D010111:Oxymorphone; C055382:naltrindole