INVESTIGATION OF THE STRUCTURAL PARAMETERS INVOLVED IN THE DELTA-OPIOID SELECTIVITY OF SEVERAL FAMILIES OF OPIOID-PEPTIDES

Three series of highly delta-opioid selective peptides are now availab le, and each family is used as template to investigate the structural parameters involved in delta-receptor recognition and in the modulatio n of the selectivity of the parent peptide. The first series includes cyclic derivatives such as Tyr-D-Pen-Gly-Phe-D-Pen(DPDPE) and Tyr-D-Pe n-Gly-Phe-Pen(DPLPE); the second are the synthetic linear constrained peptides [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(DSTBULET), Tyr-D-Ser(OtBu)-G ly-Phe-Leu-Thr(OtBu) (BUBU) and especially Tyr-D-CyS(StBu)-Gly-Phe-Leu -Thr(OtBu) (BUBUC)] and the last one the natural peptides [Tyr-D-Met-P he-His-Leu-Met-Asp-NH2(deltorphin or dermenkephalin)and Tyr-D-Ala-Phe- Asp-Val-Val-GlyNH2 ([D-Ala2] deltorphin 1)]. In the present study, the possibly of transposing some of the decisive factors of delta-selecti vity evidenced in the two other families, to the linear constrained pe ptides series was examinated. With this aim in view, residues such as Phe3, pClPhe4 or Asp were introduced in the sequence of DSTBULET, BUBU or BUBUC. Direct comparison between the biochemical profiles of the [ pClPhe4] analogs of the linear constrained peptides and their parent c ompounds shows that the addition of an electronegative atom on the Phe 4 residue of enkephalin sequences is not an absolute parameter for del ta-selectivity improvement. The hydrophobic delta-receptor subsite see ms able to receive a range of molecular volumes and electronegativitie s. By contrast, this subsite cannot interact with a Phe3 aromatic ring introduced in this series of peptides. Moreover, the results obtained with linear peptides including additional negatively charged residues demonstrate that the proposed location of the delta-receptors in a ca tionic membrane environment is not adequate to explain the selectivity profile of a number of compounds.