[D-Pen²,D-Pen⁵]enkephalin Analogues with Increased Affinity and Selectivity for δ 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.