title: Differential contribution of C-terminal regions of dermorphin and dermenkephalin to opioid-sites selection and binding potency.
abstract: Dermorphin and dermenkephalin are D-aminoacid containing peptides generated from processing of the plurifonctional biosynthetic precursor pro-dermorphin. Dermorphin, Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2 (DRM) and dermenkephalin, Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (DREK), are among the most selective and potent agonists described respectively for the mu- and delta-opioid receptors. In order to identify determinants of selectivity and high-affinity receptor binding of dermorphin and dermenkephalin, a series of analogs was investigated for their affinity at the mu- and delta-receptors in the brain. The tetrapeptide amino end of both DRM and DREK were found to display high affinity and selectivity towards mu-receptors. Substitution of the C-terminal tripeptide of DREK with that of DRM reversed the receptor selectivity of DREK from delta to mu. Replacement of the C-terminal tripeptide of DRM with the C-terminal counterpart of DREK shifted the selectivity of DRM from mu to delta. These data emphasize the critical contribution of the carboxy end of DREK to delta-selectivity. They further suggest that the potent mu-address lying in the N terminus of DREK is overwhelmed by the powerful delta-directing ability of the carboxy end. Unlike DREK, the C-terminus of DRM is not involved in opioid receptor sites selection but is important insofar as it serves to stabilize interactions of DRM with the mu-receptor binding site.
authors.affiliation: Laboratoire de Bioactivation des Peptides, Institut Jacques Monod, Université Paris 7, France.
authors.forename: S
authors.initials: S
authors.lastname: Sagan
authors.forename: M
authors.initials: M
authors.lastname: Amiche
authors.forename: A
authors.initials: A
authors.lastname: Delfour
authors.forename: A
authors.initials: A
authors.lastname: Camus
authors.forename: A
authors.initials: A
authors.lastname: Mor
authors.forename: P
authors.initials: P
authors.lastname: Nicolas
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*; D018847:Opioid Peptides; D011487:Protein Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
chemical_list: D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin; C030058:dermorphin