VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist
| Autor: | François Duhamel, Kaul R, Michel Bouvier, Sonia Brault, Nedev H, Isabelle Lahaie, J-S Joyal, David Hamel, Nikolaus Heveker, Lenka Rihakova, Sylvain Chemtob, Kim Beauregard, Przemyslaw Sapieha, Pierre Hardy, Fernand Gobeil, Xin Hou, Christiane Quiniou, Guillon G, Fadi F. Hamdan, Horacio Uri Saragovi, William D. Lubell, Zhuo Shao |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Receptors Vasopressin medicine.medical_specialty Vasopressin Allosteric modulator Physiology Muscle Relaxation Recombinant Fusion Proteins Urinary Bladder 6-Ketoprostaglandin F1 alpha In Vitro Techniques Ligands Transfection Cell Line Rats Sprague-Dawley Mice Hormone Antagonists Allosteric Regulation Physiology (medical) Internal medicine Arginine vasopressin receptor 2 Cyclic AMP medicine Animals Humans Deamino Arginine Vasopressin Receptor Vasopressin receptor G protein-coupled receptor Dose-Response Relationship Drug Chemistry Antagonist Muscle Smooth Ligand (biochemistry) Diuresis Rats Arginine Vasopressin Endocrinology Myometrium Female Oligopeptides Antidiuretic Hormone Receptor Antagonists hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 297:R1009-R1018 |
| ISSN: | 1522-1490 0363-6119 |
| DOI: | 10.1152/ajpregu.90766.2008 |
| Popis: | Vasopressin type 2 receptor (V2R) exhibits mostly important properties for hydroosmotic equilibrium and, to a lesser extent, on vasomotricity. Drugs currently acting on this receptor are analogs of the natural neuropeptide, arginine vasopressin (AVP), and hence are competitive ligands. Peptides that reproduce specific sequences of a given receptor have lately been reported to interfere with its action, and if such molecules arise from regions remote from the binding site they would be anticipated to exhibit noncompetitive antagonism, but this has yet to be shown for V2R. Six peptides reproducing juxtamembranous regions of V2R were designed and screened; the most effective peptide, cravky (labeled VRQ397), was characterized. VRQ397 was potent (IC50= 0.69 ± 0.25 nM) and fully effective in inhibiting V2R-dependent physiological function, specifically desmopressin-l-desamino-8-arginine-vasopressin (DDAVP)-induced cremasteric vasorelaxation; this physiological functional assay was utilized to avoid overlooking interference of specific signaling events. A dose-response profile revealed a noncompetitive property of VRQ397; correspondingly, VRQ397 bound specifically to V2R-expressing cells could not displace its natural ligand, AVP, but modulated AVP binding kinetics (dissociation rate). Specificity of VRQ397 was further confirmed by its inability to bind to homologous V1 and oxytocin receptors and its inefficacy to alter responses to stimulation of these receptors. VRQ397 exhibited pharmacological permissiveness on V2R-induced signals, as it inhibited DDAVP-induced PGI2generation but not that of cAMP or recruitment of β-arrestin2. Consistent with in vitro and ex vivo effects as a V2R antagonist, VRQ397 displayed anticipated in vivo aquaretic efficacy. We hereby describe the discovery of a first potent noncompetitive antagonist of V2R, which exhibits functional selectivity, in line with properties of a negative allosteric modulator. |
| Databáze: | OpenAIRE |
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