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[1-Deamino-4-Cyclohexylalanine] Arginine Vasopressin: A Potent and Specific Agonist for Vasopressin V_1b Receptors

Institut National de la Santé et de la Recherche Médicale, Unité 469 (S.D., M.B.M., M.A., G.G.), 34094 Montpellier Cedex 05, France; Medical College of Ohio (L.L.C., S.S., M.M.), Department of Biochemistry and Molecular Biology, Toledo, Ohio 43614; Division d’Endocrinologie, Diabétologie et Métabolisme, Département de Médecine (M.J.V., M.G., R.C.G.), Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland; and Department of Pharmacology (N.C.W., H.H.S.), Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: Guillon Gilles, Institut National de la Santé et de la Recherche Médicale, Unité 469, 141 rue de la Cardonille, 34094 Montpellier Cedex 05, France. E-mail: guillon{at}u469.montp.inserm.fr.

To date, there are no vasopressin (VP) agonists that exhibit a high affinity and selectivity for the VP V_1b receptor with respect to the V_1a, V₂, and oxytocin receptors. In this study, we describe the synthesis and pharmacological properties of [1-deamino-4-cyclohexylalanine] arginine vasopressin (d[Cha⁴]AVP). Binding experiments performed on various membrane preparations revealed that d[Cha⁴]AVP exhibits a nanomolar affinity for V_1b receptors from various mammalian species (rat, bovine, human). It exhibits high V_1b/V_1a and V_1b/oxytocin selectivity for rat, human, and bovine receptors. Furthermore, it exhibits high V_1b/V₂ specificity for both bovine and human vasopressin receptors. Functional studies performed on biological models that naturally express V_1b receptors indicate that d[Cha⁴]AVP is an agonist. Like VP, it stimulated basal and corticotropin-releasing factor-stimulated ACTH secretion and basal catecholamine release from rat anterior pituitary and bovine chromaffin cells, respectively. In vivo experiments performed in rat revealed that d[Cha⁴]AVP was able to stimulate both ACTH and corticosterone secretion and exhibits negligible vasopressor activity. It retains about 30% of the antidiuretic activity of VP. This long-sought selective VP V_1b receptor ligand with nanomolar affinity will allow a better understanding of V_1b-mediated VP physiological effects and is a promising new tool for V_1b receptor structure-function studies.

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