Synthesis, biology, NMR and conformation studies of the topographically constrained delta-opioid selective peptide analogs of [beta-iPrPhe(3)]deltorphin I

Replacement of Phe(3) in the endogenous F-opioid selective peptide deltorph in I with four optically pure stereoisomers of the topographically constrai ned, highly hydrophobic novel amino acid beta -isopropylphenylalanine (beta -iPrPhe) produced four pharmacologically different deltorphin I peptidomim etics. Radiolabeled ligand-binding assays and in vitro biological evaluatio n indicate that the stereoconfiguration of the iPrPhe residue plays a cruci al role in determining the binding affinity, bioactivity and selectivity of [beta -iPrPhe(3)]deltorphin I analogs: a (2S,3R) configuration of the iPrP he(3) residue in [beta -iPrPhe(3)]deltorphin I provided the most desirable biological properties with binding affinity (IC50=2 nM), bioassay potency ( IC50=1.23 nM in MVD assay) and exceptional selectivity for the delta -opioi d receptor over the mu -opioid receptor (30 000). Further conformational st udies based on two-dimensional NMR and computer-assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr (1) and (2S,3R)-beta -iPrPhe(3) residues adopt trans side-chain conformatio ns, and the linear peptide backbone favors a distorted beta -turn conformat ion.