title: Pharmacological and physiological characterization of d[Leu4, Lys8]vasopressin, the first V1b-selective agonist for rat vasopressin/oxytocin receptors.
abstract: Recently, we synthesized and characterized the first selective V(1b) vasopressin (VP)/oxytocin receptor agonist, d[Cha(4)]arginine vasopressin. However, this agonist was only selective for the human receptors. We thus decided to design a selective V(1b) agonist for the rodent species. We started from previous observations showing that modifying [deamino(1),Arg(8)]VP in positions 4 and 8 altered the rat VP/oxytocin receptor selectivity. We synthesized a series of 13 [deamino(1),Arg(8)]VP analogs modified in positions 4 and 8. Among them, one seemed very promising, d[Leu(4), Lys(8)]VP. In this paper, we describe its pharmacological and physiological properties. This analog exhibited a nanomolar affinity for the rat, human, and mouse V(1b) VP receptors and a strong V(1b) selectivity for the rat species. On AtT20 cells stably transfected with the rat V(1b) receptor, d[Leu(4), Lys(8)]VP behaved as a full agonist on both phospholipase C and MAPK assays. Additional experiments revealed its ability to induce the internalization of enhanced green fluorescent protein-tagged human and mouse V(1b) receptors as expected for a full agonist. Additional physiological experiments were performed to further confirm the selectivity of this peptide. Its antidiuretic, vasopressor, and in vitro oxytocic activities were weak compared with those of VP. In contrast, used at low doses, its efficiency to stimulate adrenocorticotropin or insulin release from mouse pituitary or perfused rat pancreas, respectively, was similar to that obtained with VP. In conclusion, d[Leu(4), Lys(8)]VP is the first selective agonist available for the rat V(1b) VP receptor. It will allow a better understanding of V(1b) receptor-mediated effects in rodents.
authors.affiliation: Institut de Génomique Fonctionnelle, Département d'Endocrinologie, 141 rue de la Cardonille, 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: Gyslaine
authors.initials: G
authors.lastname: Bertrand
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Cheng
authors.forename: Stoytcho
authors.initials: S
authors.lastname: Stoev
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: Nga
authors.initials: N
authors.lastname: Wo
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Brossard
authors.forename: Claudine
authors.initials: C
authors.lastname: Serradeil-Le Gal
authors.forename: Maurice
authors.initials: M
authors.lastname: Manning
authors.forename: Gilles
authors.initials: G
authors.lastname: Guillon
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D007774:Lactation; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008236:Lypressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000819:agonists* / Q000187:drug effects / Q000235:genetics; D017483:Receptors, Vasopressin / Q000819:agonists*; D011994:Recombinant Proteins / Q000819:agonists / Q000187:drug effects; D014162:Transfection
chemical_list: D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D011994:Recombinant Proteins; C005659:vasopressin, 4-Leu-8-Lys-; D008236:Lypressin; D000262:Adenylyl Cyclases