Structural requirements for substitutions in delta opioid receptor selective, cyclic tetrapeptide dermorphin analogs: Divergence from related pentapeptide enkephalin analogs.

The conformationally restricted, delta opioid receptor selective tetrapeptide H-Tyr-D-$\rm C\overline{ys-Phe-{\it D}-Pe}nOH,$ cyclized by disulfide formation between side chains of residues 2 and 4, was modified at each residue to allow comparison with the cyclic disulfide-containing pentapeptide analogs of (D-Pen$\sp2$, D-Pen$\sp5$) enkephalin (DPDPE). Analogs of the template tetrapeptide were designed to explore the biological consequences of substitution of amino acids with varying steric, electronic, lipophilic, and/or chiral properties at each residue. Effects on binding affinity and selectivity at mu and delta opioid receptors and on bioassay potency were evaluated. Analogs investigating the effect of the orientation and the nature of side chain aromatic functional moieties were prepared. Modifications which were expected to influence backbone and side chain conformation at each residue, as well as variation in the cyclic portion of the molecule, also were examined. Data indicated that structure-activity relationships developed for pentapeptide enkephalins often were inapplicable to the tetrapeptide series. In general, where direct comparisons were possible, structural requirements for the Phe$\sp3$ residue in this tetrapeptide series were less stringent than in the related pentapeptide series. These findings suggest possible differences in the manner in which the Phe$\sp3$ residue of dermorphin-like tetrapeptides and the Phe$\sp4$ residue of enkephalin-like pentapeptides interact at delta opioid receptors; however, other interpretations are not excluded. Distinctions between the series in elements of the binding interaction also were notable at other residues. These peptides lack the central glycine residue of enkephalin analogs, therefore resembling dermorphin, and can be expected to possess a higher degree of rigidity and structural definition, an effect to which results may be attributed. They thereby represent a more credible series for analysis of the structural and conformational features required for peptide ligand binding at the opioid receptor types. In addition, comparison of the effects of analogous modification between the cyclic tetrapeptides and the restricted pentapeptides allows examination of the proposal that different subsites of the delta receptor may be involved in the binding of the two series.