COMPARISON OF CYCLIC DELTA-OPIOID PEPTIDES WITH NONPEPTIDE 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 m olecular template for a conformational search and analysis of delta-se lective opioid peptides. It was assumed that the tyramine moiety plays the same role for delta-opioid receptor recognition in both peptide a nd non-peptide ligands. Using 20 reported low-energy conformations of Tyr-cyclo[D-Cys-D-Pen]-OH (JOM-13) for comparison, the geometrical rel ationship of the two aromatic rings present in SIOM was used for the i dentification 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 back bones. To evaluate the two models, a conformational search of two othe r known delta-selective ligands, [D-Pen(2),D-Pen(5)]enkephalin (DPDPE) and [D-Pen(2),L-Pen(5)]enkephalin (DPLPE) was performed, using;he geo metrical relationship of the two aromatic rings defined in the two rec eptor-binding models as a molecular template. Among the conformations generated from the molecular simulation, low-energy conformers of DPDP E and DPLPE conforming to models I and II were identified. Unlike mode l I, conformers of DPDPE and DPLPE that fit model II contain a cis ami de bond in the Gly(3) residue.