DEVELOPMENT OF A MODEL FOR THE DELTA-OPIOID RECEPTOR PHARMACOPHORE .1. CONFORMATIONALLY RESTRICTED TYR(1) REPLACEMENTS IN THE CYCLIC DELTA-RECEPTOR SELECTIVE TETRAPEPTIDE TYR-C[D-CYS-PHE-D-PEN]OH (JOM-13)

A series of analogues of the conformationally restricted delta opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM 13) was prepared in which the conformationally labile Tyr residue was replaced with several less flexible tyrosine analogues. Among these tyrosine analogues were the bicyclic structures 1,2,3,4,-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (HO-Tic), 2-amino-6-hydroxytetralin-2-carboxylic acid (Hat), and 2-amino-5-hydroxyindan-2-carboxylic acid (Hai) in which rotations about the C-alpha-C-beta and C-beta-C-gamma bonds are restricted due to cyclization of the side chain to the backbone. Also examined were analogues in which tyrosine was replaced with either trans-3-(4'-hydroxyphenyl)proline (t-Hpp) or cis-3-(4'-hydroxyphenyl)proline (c-Hpp), residues in which rotations about C-alpha-C-beta, but not C-beta-C-gamma, are restricted. Both the t-Hpp(1) and c-Hpp(1) analogues displayed delta receptor binding affinity similar to the parent Tyr(1)-containing peptide, while the D-Hat(1),L-Hat(1), and L-Hai(1) analogues exhibited somewhat lower affinity. The results observed for the t-Hpp(1) and c-Hpp(1) analogues are particularly significant since these two residues have little accessible conformational space in common. Since the binding conformation of residue 1 must be included in this limited conformational intersection, its elucidation is facilitated. Bioassay results from guinea pig ileum and mouse vas deferens preparations are in general agreement with the binding results; however some potency discrepancies are observed. These discrepancies may reflect different selectivities among delta receptor subtypes for the analogues or may represent differing efficacies among these conformationally restricted peptides. The conformational properties of the parent tetrapeptide and the residue 1-modified analogues were studied by molecular mechanics computations. All these peptides share a common rigid tripeptide cycle with a single energetically preferred backbone conformation and three different conformers of the D-Cys, D-Pen disulfide bridge, two of which are observed in the solid state and in aqueous solution, as previously determined from X-ray crystallography and H-1 NMR spectroscopy data (Lomize, A.; et al. J. Am. Chem. Soc. 1994, 116, 429-436). All the peptides have similar sets of low-energy conformations of their common flexible elements, the Phe(3) side chain and the peptide group between the first residue and the rigid tripeptide cycle. However, possible conformations of the first residue differ and depend on the covalent constraints incorporated into the side chain. Analysis of conformation-activity relationships obtained for these peptides allows the determination of some of the conformational requirements for their interaction with the delta opioid receptor. First, the side chain conformer of residue 1 in the delta receptor-bound state is determined to be trans (chi(1) similar to 180 degrees). Second, an extended conformation of the exocyclic peptide group (both psi of residue 1 and phi of D-Cys(2) torsion angles are similar to 160 degrees) is identified as providing the mutual arrangement of the first residue and the tripeptide cycle required for delta receptor binding.