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Chemical Compound Review

Relcovaptan     (2S)-1-[[(2R,3S)-5-chloro-3- (2...

Synonyms: CHEMBL419667, SureCN4387208, CHEBI:241205, AC1Q5IRB, SR-49059, ...
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Disease relevance of Relcovaptan

  • DESIGN: The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion [1].
  • In contrast, the V(1A) receptor selective antagonist, SR 49059, and the V(2) receptor selective antagonist, SR 121463A, did not potently inhibit oxytocin-induced [Ca(2+)](i) increase and hyperplasia [2].
  • The administration of SR 49059 significantly reduced cerebral vasospasm [3].
  • After single and repeated iv or icv administration, we studied the antiemetic properties of SR 49059 on cisplatin-induced emesis in piglets [4].
  • Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease [5].

High impact information on Relcovaptan

  • Furthermore, SR 49059 inhibited AVP-induced human platelet aggregation with an IC50 value of 3.7 +/- 0.4 nM, while OPC-21268 was inactive up to 20 microM [6].
  • SR 49059 showed high affinity for V1a receptors from rat liver (Ki = 1.6 +/- 0.2) and human platelets, adrenals, and myometrium (Ki ranging from 1.1 to 6.3 nM) [6].
  • We now show that the cell surface expression and function (binding of the agonist) of the mainly ER-retained wild-type murine vasopressin V2 receptor GFP fusion protein (mV2R.GFP) is restored by the vasopressin receptor antagonists SR49059 and SR121463B with EC50 values similar to their KD values [7].
  • The F225C, F308C, and K128C mutants of the V1a receptor were expressed in COS-7 or Chinese hamster ovary cells, and their pharmacological properties toward SR49059 and its sulfydryl-reactive analogues were analyzed [8].
  • To identify the binding site of the human V1a vasopressin receptor for the selective nonpeptide antagonist SR49059, we have developed a site-directed irreversible labeling strategy that combines mutagenesis of the receptor and use of sulfydryl-reactive ligands [8].

Chemical compound and disease context of Relcovaptan

  • Intravenous bolus injections of 10 pmol/kg body weight of vasopressin (Period 1) and of 50 pmol/kg body weight of oxytocin (Period 2) were given 1 h before and 1, 2 and 4 h after oral administration of 0 (placebo), 25, 75 or 200 mg of SR 49059 [9].
  • Dimethyl sulfoxide (DMSO) is widely used as a solvent for other drugs, i.e., for the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) and the V1a receptor-antagonist SR49059, to reduce brain edema [10].

Biological context of Relcovaptan

  • Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors [8].
  • This raises the possibility that, instead of acting as a pharmacological chaperone by favoring proper maturation of the receptors, SR49059 could mediate its action on R137H V2R by preventing its endocytosis [11].
  • In patients, SR49059 decreased 24- h urine volume (11.9 +/- 2.3 to 8.2 +/- 2.0 L; P = 0.005) and water intake (10.7 +/- 1.9 to 7.2 +/- 1.6 L; P < 0.05) [12].
  • Effects of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist, on vasopressin-induced vasoconstriction in humans [13].
  • CONCLUSION: SR 49059 given orally once a day for 7 days to patients with RP showed favourable effects compared with placebo on finger systolic pressure and temperature recovery after cold immersion, without inducing side-effects [14].

Anatomical context of Relcovaptan


Associations of Relcovaptan with other chemical compounds


Gene context of Relcovaptan

  • A radioligand binding study showed that SR49059 and OPC-21268 potently inhibited [3H]AVP binding to the cloned mouse V1a receptor, with Ki values of 27 and 510 nM, respectively, whereas SSR149415 potently inhibited [3H]AVP binding to the cloned mouse V1b receptor with a Ki value of 110 nM [20].
  • Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype [5].
  • Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man [5].
  • 3. The [Ca2+]i response induced by 1 microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists (SR 49059 and SR 121463A, respectively) [21].
  • Pharmacological characterization of the transfected human AVP receptors was undertaken by measuring the relative ability of nonpeptide AVP receptor antagonists, YM087, OPC-21268, OPC-31260, SR 49059 and SR 121463A, to inhibit binding of [3H]-AVP [22].

Analytical, diagnostic and therapeutic context of Relcovaptan


  1. Evidence for a role of vasopressin in the control of aldosterone secretion in primary aldosteronism: in vitro and in vivo studies. Perraudin, V., Delarue, C., Lefebvre, H., Do Rego, J.L., Vaudry, H., Kuhn, J.M. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  2. Pharmacologic characterization of the oxytocin receptor in human uterine smooth muscle cells. Tahara, A., Tsukada, J., Tomura, Y., Wada, K., Kusayama, T., Ishii, N., Yatsu, T., Uchida, W., Tanaka, A. Br. J. Pharmacol. (2000) [Pubmed]
  3. Participation of vasopressin in the development of cerebral vasospasm in a rat model of subarachnoid haemorrhage. Trandafir, C.C., Nishihashi, T., Wang, A., Murakami, S., Ji, X., Kurahashi, K. Clin. Exp. Pharmacol. Physiol. (2004) [Pubmed]
  4. A nonpeptide vasopressin V(1a) receptor antagonist, SR 49059, does not prevent cisplatin-induced emesis in piglets. Grélot, L., Girod, V., Dapzol, J., Maffrand, J.P., Serradeil-Le Gal, C. Fundamental & clinical pharmacology. (2001) [Pubmed]
  5. Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. Serradeil-Le Gal, C., Wagnon, J., Valette, G., Garcia, G., Pascal, M., Maffrand, J.P., Le Fur, G. Prog. Brain Res. (2002) [Pubmed]
  6. Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors. Serradeil-Le Gal, C., Wagnon, J., Garcia, C., Lacour, C., Guiraudou, P., Christophe, B., Villanova, G., Nisato, D., Maffrand, J.P., Le Fur, G. J. Clin. Invest. (1993) [Pubmed]
  7. Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. Wüller, S., Wiesner, B., Löffler, A., Furkert, J., Krause, G., Hermosilla, R., Schaefer, M., Schülein, R., Rosenthal, W., Oksche, A. J. Biol. Chem. (2004) [Pubmed]
  8. Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors. Tahtaoui, C., Balestre, M.N., Klotz, P., Rognan, D., Barberis, C., Mouillac, B., Hibert, M. J. Biol. Chem. (2003) [Pubmed]
  9. Inhibitory effects of SR 49059 on oxytocin-and vasopressin-induced uterine contractions in non-pregnant women. Steinwall, M., Bossmar, T., Gaud, C., Akerlund, M. Acta obstetricia et gynecologica Scandinavica. (2004) [Pubmed]
  10. Effect of dimethyl sulfoxide on blood-brain barrier integrity following middle cerebral artery occlusion in the rat. Kleindienst, A., Dunbar, J.G., Glisson, R., Okuno, K., Marmarou, A. Acta Neurochir. Suppl. (2006) [Pubmed]
  11. Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Bernier, V., Lagacé, M., Lonergan, M., Arthus, M.F., Bichet, D.G., Bouvier, M. Mol. Endocrinol. (2004) [Pubmed]
  12. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. Bernier, V., Morello, J.P., Zarruk, A., Debrand, N., Salahpour, A., Lonergan, M., Arthus, M.F., Laperrière, A., Brouard, R., Bouvier, M., Bichet, D.G. J. Am. Soc. Nephrol. (2006) [Pubmed]
  13. Effects of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist, on vasopressin-induced vasoconstriction in humans. Weber, R., Pechère-Bertschi, A., Hayoz, D., Gerc, V., Brouard, R., Lahmy, J.P., Brunner, H.R., Burnier, M. Hypertension (1997) [Pubmed]
  14. Effect of SR 49059, a V1a vasopressin receptor antagonist, in Raynaud's phenomenon. Hayoz, D., Bizzini, G., Noël, B., Depairon, M., Burnier, M., Fauveau, C., Rouillon, A., Brouard, R., Brunner, H.R. Rheumatology (Oxford, England) (2000) [Pubmed]
  15. Effect of a new, potent, non-peptide V1a vasopressin antagonist, SR 49059, on the binding and the mitogenic activity of vasopressin on Swiss 3T3 cells. Serradeil-Le Gal, C., Bourrié, B., Raufaste, D., Carayon, P., Garcia, C., Maffrand, J.P., Le Fur, G., Casellas, P. Biochem. Pharmacol. (1994) [Pubmed]
  16. Potent inhibitory effect of SR 49059, an orally active non-peptide vasopressin VIa receptor antagonist, on human arterial coronary bypass graft. Liu, J.J., Chen, J.R., Buxton, B.B., Johnston, C.I., Burrell, L.M. Clin. Sci. (1995) [Pubmed]
  17. V2 receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs. Bernat, A., Hoffmann, P., Dumas, A., Serradeil-le Gal, C., Raufaste, D., Herbert, J.M. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  18. Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Akerlund, M., Bossmar, T., Brouard, R., Kostrzewska, A., Laudanski, T., Lemancewicz, A., Serradeil-Le Gal, C., Steinwall, M. British journal of obstetrics and gynaecology. (1999) [Pubmed]
  19. Characterisation of the biological effects of neurohypophysial peptides on seminiferous tubules. Harris, G.C., Nicholson, H.D. J. Endocrinol. (1998) [Pubmed]
  20. Vasopressin stimulates insulin release from islet cells through V1b receptors: a combined pharmacological/knockout approach. Oshikawa, S., Tanoue, A., Koshimizu, T.A., Kitagawa, Y., Tsujimoto, G. Mol. Pharmacol. (2004) [Pubmed]
  21. V1a- and V2-type vasopressin receptors mediate vasopressin-induced Ca2+ responses in isolated rat supraoptic neurones. Gouzénes, L., Sabatier, N., Richard, P., Moos, F.C., Dayanithi, G. J. Physiol. (Lond.) (1999) [Pubmed]
  22. Pharmacological characterization of the human vasopressin receptor subtypes stably expressed in Chinese hamster ovary cells. Tahara, A., Saito, M., Sugimoto, T., Tomura, Y., Wada, K., Kusayama, T., Tsukada, J., Ishii, N., Yatsu, T., Uchida, W., Tanaka, A. Br. J. Pharmacol. (1998) [Pubmed]
  23. The relationship among carbon dioxide pneumoperitoneum, vasopressin release, and hemodynamic changes. Mann, C., Boccara, G., Pouzeratte, Y., Eliet, J., Serradel-Le Gal, C., Vergnes, C., Bichet, D.G., Guillon, G., Fabre, J.M., Colson, P. Anesth. Analg. (1999) [Pubmed]
  24. The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor. Steinwall, M., Bossmar, T., Brouard, R., Laudanski, T., Olofsson, P., Urban, R., Wolff, K., Le-Fur, G., Akerlund, M. Gynecol. Endocrinol. (2005) [Pubmed]
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