title: Urotensin-II receptor ligands. From agonist to antagonist activity.
abstract: Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand of a G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have recently identified both a superagonist of hU-II termed P5U and the compound termed urantide, which is the most potent UT receptor peptide antagonist described to date. Our previous conformational studies showed that hU-II and its analogues with agonist activity adopt a well-defined type II' beta-hairpin structure in anisotropic SDS membrane-like environment. This structural arrangement allows tight contact among the Trp7, Lys8, and Tyr9 side chains, which is fundamental to obtain full agonist activity. Here, we report an extensive SAR study on new analogues with agonist/antagonist activity on UT receptor. We investigated their biological activity and performed a conformational analysis by spectroscopic and computational methods. Our goal is to obtain a structure-based model able to explain the agonist/antagonist functional switching of these ligands.
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, I-80131 Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Teresa
authors.initials: T
authors.lastname: Lama
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Paolo
authors.initials: P
authors.lastname: Santicioli
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Maggi
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008823:Micelles; D008958:Models, Molecular; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012967:Sodium Dodecyl Sulfate; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008823:Micelles; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; C466635:aspartyl-cyclo(penicillamyl-phenylalanyl-tryptophyl-lysyl-tyrosyl-cysteinyl)valine; D012967:Sodium Dodecyl Sulfate; C029677:urotensin II