[Cyclic] [D-Pen2,D-Pen5]enkephalin analogs with increased affinity and selectivity for .delta.-opioid receptors

• Published in: Journal of medicinal chemistry 1990-01, Vol.33 (1), p.249-253
• Main Authors: Toth, Geza, Kramer, Thomas H, Knapp, Richard, Lui, George, Davis, Peg, Burks, Thomas F, Yamamura, Henry I, Hruby, Victor J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Aminoacids, peptides. Hormones. Neuropeptides; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Brain - metabolism; Chemical Phenomena; Chemistry; Enkephalin, D-Penicillamine (2,5); Enkephalins - chemical synthesis; Enkephalins - metabolism; Enkephalins - pharmacology; Fundamental and applied biological sciences. Psychology; Guinea Pigs; Ileum - physiology; Male; Mice; Molecular Sequence Data; Muscle Contraction - drug effects; Proteins; Radioligand Assay; Rats; Receptors, Opioid - drug effects; Receptors, Opioid - physiology; Receptors, Opioid, delta; Structure-Activity Relationship; Vas Deferens - physiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00163a041

The conformationally 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 delta opioid receptor was greater than that of the parent peptide. The analogues possessed greater potency and affinity for the delta 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(mu)/IC50(delta) = 574), being about 5-fold more delta 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 (IC50(GPI)/IC50(MVD) = 17,374), making it nearly 9-fold more selective than DPDPE in direct comparisons using the same assay conditions.