title: Design and synthesis of the first selective agonists for the rat vasopressin V(1b) receptor: based on modifications of deamino-[Cys1]arginine vasopressin at positions 4 and 8.
abstract: The neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT) mediate a wide variety of peripheral and central physiological and behavioral effects by acting on four different G-protein coupled receptors, termed V1a (vascular), V1b (pituitary), V2 (renal), and OT (uterine). We recently reported that d[Cha4]AVP (A), d[Leu4]AVP (B), d[Orn4]AVP (C), and d[Arg4]AVP (D) have high affinity and are selective agonists for the human V1b receptor. However, peptides A-D were subsequently shown to be potent antidiuretic agonists in the rat and are, thus, not selective V1b agonists in the rat. Peptides A-D served as leads for the studies reported here. They were modified at position 8 by Lys, ornithine (Orn), diaminobutyric acid (Dab), and diaminopropionic acid (Dap) to give d[Cha4,Lys8]VP (1), d[Cha4,Orn8]VP (2), d[Cha4,Dab8]VP (3), d[Cha4,Dap8]VP (4), d[Leu4,Lys8]VP (5), d[Leu4,Orn8]VP (6), d[Leu4,Dab8]VP (7), d[Leu4,Dap8]VP (8), d[Orn4,Lys8]VP (9), d[Orn4,Orn8]VP (10), d[Arg4,Lys8]VP (11), d[Arg4,Orn8]VP (12), and d[Arg4,Dab8]VP (13). All peptides were synthesized by the Merrifield solid-phase method. Their binding and functional properties were evaluated in rat AVP V1a, V1b, and V2 receptors and on the rat OT receptor expressed either in native tissues or in stably transfected cells. They were also examined in rat vasopressor, antidiuretic, and in in vitro (no Mg++) oxytocic assays. Functional studies performed on chinese hamster ovary cells expressing the different AVP/OT receptors confirm that d[Cha4,Lys8]VP (1), d[Cha4,Dab8]VP (3), d[Leu4,Lys8]VP (5), and d[Leu4,Dap8]VP (8) are the first selective agonists for the rat V1b receptor. These selective V1b agonists are promising new tools for studies of the role of the V1b receptor in the rat.
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR 5203-INSERM U.661, Université Montpellier I et II, 34094 Montpellier Cedex 05, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Pena
authors.forename: Brigitte
authors.initials: B
authors.lastname: Murat
authors.forename: Miguel
authors.initials: M
authors.lastname: Trueba
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ventura
authors.forename: Nga C
authors.initials: NC
authors.lastname: Wo
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Cheng
authors.forename: Stoytcho
authors.initials: S
authors.lastname: Stoev
authors.forename: Gilles
authors.initials: G
authors.lastname: Guillon
authors.forename: Maurice
authors.initials: M
authors.lastname: Manning
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D050034:Antidiuretic Agents / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010120:Oxytocics / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists; D011869:Radioligand Assay; D051381:Rats; D018045:Receptors, Oxytocin / Q000819:agonists; D017483:Receptors, Vasopressin / Q000819:agonists*; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D050034:Antidiuretic Agents; D007295:Inositol Phosphates; D009842:Oligopeptides; D010120:Oxytocics; D010456:Peptides, Cyclic; D020033:Protein Isoforms; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D000262:Adenylyl Cyclases