naltrindole and 7-spiroindanyloxymorphone

The 14-hydroxy group is known to increase the antagonist potency of mu-selective opioid ligands. To investigate the role of this group at the delta opioid receptor, the 14-desoxy analogues (7 and 9) of the delta-selective ligands, naltrindole (1, NTI) and spiroindanyloxymorphone (2, SIOM), have been synthesized and tested. The in vitro pharmacologic activities of 7 and 9 suggest that the 14-hydroxy group plays an important role in determining the delta selectivity and potency of NTI and SIOM.

Topics: Animals; Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Muscle Contraction; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Oxymorphone; Receptors, Opioid, delta; Spiro Compounds; Vas Deferens

Through arylation of 6-keto opiates with diaryliodonium iodide, a series of 7-aryl opiates (3-8) have been prepared in an effort to investigate the effect of conformational mobility of the delta "address" moiety on opioid agonist and antagonist potencies. Evaluation of the ligands in the mouse vas deferens and guinea pig ileum preparations revealed that they were less potent and less selective than the conformationally constrained ligands, naltrindole (1, NTI) and 7-(spiroindanyl)oxymorphone (2, SIOM), at delta opioid receptors. It is concluded that the coplanarity of the address moiety with the C ring of the morphinan structure enhances delta antagonist potency and selectivity.

Topics: Animals; Electric Stimulation; Guinea Pigs; Ileum; In Vitro Techniques; Ligands; Male; Mice; Models, Molecular; Molecular Conformation; Morphinans; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Oxymorphone; Pain Measurement; Receptors, Opioid, delta; Spiro Compounds; Vas Deferens

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