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Pharmacological and Physiological Characterization of d[Leu⁴, Lys⁸]Vasopressin, the First V_1b-Selective Agonist for Rat Vasopressin/Oxytocin Receptors

Institut de Génomique Fonctionnelle, Départements d’Endocrinologie (A.P., B.M., G.G.) et de Neurophysiologie (G.Be.); Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 661 (A.P., B.M., G.G., G.Be.), 34094 Montpellier, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5203 (A.P., B.M., G.G, G.Be.), 34094 Montpellier, France; Department of Biochemistry and Molecular Biology (M.T.), Faculty of Science and Technology, University of the Basque Country, 48080 Bilbao, Spain; Department of Biochemistry and Cancer Biology (L.L.C., S.S., M.M.), University of Toledo College of Medicine, Toledo, Ohio 43614; Department of Pharmacology (H.H.S., N.W.), Weill Medical College of Cornell University, New York, New York 10021; Sanofi-Aventis (G.Br., C.S.L), 31100 Toulouse, France; Institut Cochin (M.A.V.), Département d’Endocrinologie Metabolisme et Cancer, Université Paris Descartes, CNRS, UMR 8104, 75016 Paris, France; and INSERM (M.A.V.), Unité 567, 75012 Paris, France

Address all correspondence and requests for reprints to: Gilles Guillon, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier Cedex 05, France. E-mail: gilles.guillon{at}igf.cnrs.fr.

Recently, we synthesized and characterized the first selective V_1b vasopressin (VP)/oxytocin receptor agonist, d[Cha⁴]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 [deamino¹,Arg⁸]VP in positions 4 and 8 altered the rat VP/oxytocin receptor selectivity. We synthesized a series of 13 [deamino¹,Arg⁸]VP analogs modified in positions 4 and 8. Among them, one seemed very promising, d[Leu⁴, Lys⁸]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[Leu⁴, Lys⁸]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[Leu⁴, Lys⁸]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.

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