SYNTHESIS AND BIOLOGICAL PROPERTIES OF BETA-MEPHE(3) ANALOGS OF DELTORPHIN-I AND DERMENKEPHALIN - INFLUENCE OF BIASED CHI(1) OF PHE(3) RESIDUES ON PEPTIDE RECOGNITION FOR DELTA-OPIOID RECEPTORS

Using the method of conformational constraint, we have designed and sy nthesized analogues of deltorphin I and dermekephalin containing each of the four stereoisomers (2S,3S; 2S,3R; 2R,3S, 2R,3R) of the unusual amino acid beta-methylphenylalanine in position three, The potency and selectivity of these analogues were evaluated by radioreceptor bindin g assays in the rat brain using [H-3]CTOP (mu-ligand) and [(3)Hl[p-ClP he(4)]DPDPE(delta-ligand), and by bioassay using the mouse vas deferen s (delta-receptor assay) and guinea pig ileum (mu-receptor assay) assa ys. The substitution of a beta-MePhe for Phe(3) in deltorphin I and de rmenkephalin has a large and variable effect on the bioactivities of t he synthesized analogues. The synthesized analogues are somewhat less potent than the native peptides. Both [(2S,3R)-beta-MePhe(3)]deltorphi n and [(2S,3R)-beta-MePhe(3)]dermenkephalin are more selective, howeve r, and interact essentially specifically with the receptor in the bind ing: assays and bioassays. The bioassay data ii vitro of the synthesiz ed analogues of deltorphin I and dermenkephalin follow: the same gener al trends as the receptor binding data. These results demonstrate that topographical modifications of the side-chain conformation of critica l structural moieties in a ligand can significantly modulate both the potency and receptor selectivity for ligands that have multiple sites of biological activity, and they illustrate that this approach has gen eral application to peptide and peptidomimetic ligand design.