[D-PEN2,D-PEN5]ENKEPHALIN ANALOGS WITH INCREASED AFFINITY AND SELECTIVITY FOR DELTA-OPIOID RECEPTORS

The conformationaUy restricted, cyclic disulfide-containing enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by halogenation (F, Cl, Br, I) of the phenylalanine-4 residue in the para position. The potency and selectivity of these analogues for the δ opioid receptor was greater than that of the parent peptide. The analogues possessed greater potency and affinity for the δ receptors than DPDPE in the mouse vas deferens assay and in radioreceptor assays (against [3H]DPDPE), respectively. [p-ClPhe4]DPDPE was the most selective in the radioligand binding assays(IC50(δ) = 574), being about 5-fold more δ opioid receptor selective than DPDPE in this assay, whereas [p-IPhe4]DPDPE was the most selective in the classical bioassay systems using the mouse vas deferens and guinea pig ileum assays (IC50GPI)/IC50MVD) = 17374), making it nearly 9-fold more selective than DPDPE in direct comparisons using the same assay conditions. © 1990, American Chemical Society. All rights reserved.