Investigations on the properties of the high delta and mu affinities and selectivities of deltorphins and dermorphin, respectively, was undertaken with nearly 150 synthetic analogues to analyze the interaction of opioids with brain receptors. Our data with deltorphins A, B, and C underscored the following conclusions concerning the requirement for delta affinity and selectivity: (1) reversal of selectivity occurred upon the stepwise N- terminal shift of the C-terminal Asp residue; (2) the lipophilicity of the side-chain of the amino acid residue at position 6 had little bearing on receptor interaction; (3) bulky protective groups on residues 4 or 7, or both, diminished binding to delta receptors; (4) para halogenation of the benzyl ring of phenylalanine enhanced both brain delta receptor binding and bioactivity as measured by use of pharmacological paradigms, however, but not the same halogen for both assays, which further serves to demonstrate differences between central and peripheral opioid receptors; on the other hand, amino or nitro derivatives were detrimental for binding and an anomalous correlation of receptor mu affinity to the lipophilicity and GPI bioactivity; (5) substitutions of phenylalanine suggested that the delta receptor is amendable to ligands in which the aromatic benzyl ring lies perpendicular to, but not in, the plane of the peptide backbone; (6) molecules extended from the N-terminus or bridged between residue 1 4 exhibited reduced selectivity, yet provided evidence that the delta receptor can accommodate a significantly modified tyrosine residue. Data with dermorphins opened new vistas for the production of super agonists with enhanced mu binding activity. Preliminary computer modeling of the deltorphins tends to confirm the nuclear magnetic resonance analyses that these peptides exhibit a degree of structural integrity in solution; i.e., the N-terminal region forms and type II beta-turn, in which D-alanine and phenylalanine are critical residues and the formation of a folded structure occurs through internal hydrogen bonds to assist in stabilization of its flexible nature. Down regulation of opioid receptors in neuroblastoma cell cultures suggested that G-proteins and unidentified factors are responsible for the modulatory response that may be involved in drug addiction.
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