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Nonpeptide Antagonists for Vasopressin Receptors

Pharmacology of SR 121463A, A New Potent and Highly Selective V2 Receptor Antagonist

  • Chapter
Vasopressin and Oxytocin

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 449))

Abstract

Involvement of AVP in several pathological states is now established and specific modulation of the different AVP receptor subtypes (V1a, V1b and V2) offers new clinical perspectives for treating major diseases. Recent years have marked a turning point with the design and the use of the first nonpeptide vasopressin receptor antagonists expressing various selectivity profile. In that field, we report here the characterization of SR 121463A a highly selective, orally-active antagonist of vasopressin V2 receptors in several models in vitro and in vivo. This compound displayed competitive nanomolar affinity for V2 receptors in various species including man and exhibited a highly selective AVP V2 profile. In vitro, SR 121463A potently antagonized AVP-stimulated adenylyl cyclase activity in human kidney preparations (K i = 0.26 ± 0.04 nM) without any intrinsic agonistic effect. In normally-hydrated rats, SR 121463A induced dose-dependent powerful and long-lasting aquaresis after intravenous (0.003 to 0.3 mg/kg) or oral (0.03 to 10 mg/kg) administration. The action of SR 121463A is purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In vasopressin-deficient Brattleboro rats, SR 121463A is devoid of any V2 antidiuretic agonist properties. In addition, this compound potently antagonized DDAVP extrarenal V2 effects on hemostasis factor release (FVIII, vW and t-PA) in dogs (ID 50 ≈ 10 μg/kg i.v.). Thus, SR 121463A is the most potent and selective, orally-active V2 antagonist yet described. It is a useful ligand for exploring V2 receptors and the therapeutical usefulness of pure V2 aquaretic agents in several water-retaining diseases and congestive heart failure.

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Authors and Affiliations

  1. Exploratory Research Department, Sanofi Recherche, 31036, Toulouse Cedex, France

    C. Serradeil-Le Gal

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  1. C. Serradeil-Le Gal
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Editors and Affiliations

  1. McGill University, Montreal, Quebec, Canada

    Hans H. Zingg  & Charles W. Bourque  & 

  2. University of Montreal, Montreal, Quebec, Canada

    Daniel G. Bichet

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© 1998 Springer Science+Business Media New York

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Gal, C.SL. (1998). Nonpeptide Antagonists for Vasopressin Receptors. In: Zingg, H.H., Bourque, C.W., Bichet, D.G. (eds) Vasopressin and Oxytocin. Advances in Experimental Medicine and Biology, vol 449. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4871-3_54

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  • DOI: https://doi.org/10.1007/978-1-4615-4871-3_54

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7210-3

  • Online ISBN: 978-1-4615-4871-3

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