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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Jul 1993; 92(1): 224–231.
PMCID: PMC293574

Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors.


SR 49059, a new potent and selective orally active, nonpeptide vasopressin (AVP) antagonist has been characterized in several in vitro and in vivo models. 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). The previously described nonpeptide V1 antagonist, OPC-21268, was almost inactive in human tissues at concentrations up to 100 microM. SR 49059 exhibited much lower affinity (two orders of magnitude or more) for AVP V2 (bovine and human), V1b (human), and oxytocin (rat and human) receptors and had no measurable affinity for a great number of other receptors. In vitro, AVP-induced contraction of rat caudal artery was competitively antagonized by SR 49059 (pA2 = 9.42). 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. In vivo, SR 49059 inhibited the pressor response to exogenous AVP in pithed rats (intravenous) and in conscious normotensive rats (intravenous and per os) with a long duration of action (> 8 h at 10 mg/kg p.o). In all the biological assays used, SR 49059 was devoid of any intrinsic agonistic activity. Thus, SR 49059 is the most potent and selective nonpeptide AVP V1a antagonist described so far, with marked affinity, selectivity, and efficacy toward both animal and human receptors. With this original profile, SR 49059 constitutes a powerful tool for exploring the therapeutical usefulness of a selective V1a antagonist.

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  • Jard S. Vasopressin antagonists. Adv Nephrol Necker Hosp. 1987;16:1–15. [PubMed]
  • Birnbaumer M, Seibold A, Gilbert S, Ishido M, Barberis C, Antaramian A, Brabet P, Rosenthal W. Molecular cloning of the receptor for human antidiuretic hormone. Nature. 1992 May 28;357(6376):333–335. [PubMed]
  • Lolait SJ, O'Carroll AM, McBride OW, Konig M, Morel A, Brownstein MJ. Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature. 1992 May 28;357(6376):336–339. [PubMed]
  • Morel A, O'Carroll AM, Brownstein MJ, Lolait SJ. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature. 1992 Apr 9;356(6369):523–526. [PubMed]
  • Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H. Structure and expression of a human oxytocin receptor. Nature. 1992 Apr 9;356(6369):526–529. [PubMed]
  • Rosenthal W, Seibold A, Antaramian A, Lonergan M, Arthus MF, Hendy GN, Birnbaumer M, Bichet DG. Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature. 1992 Sep 17;359(6392):233–235. [PubMed]
  • László FA, László F, Jr, De Wied D. Pharmacology and clinical perspectives of vasopressin antagonists. Pharmacol Rev. 1991 Mar;43(1):73–108. [PubMed]
  • Manning M, Sawyer WH. Discovery, development, and some uses of vasopressin and oxytocin antagonists. J Lab Clin Med. 1989 Dec;114(6):617–632. [PubMed]
  • Yamamura Y, Ogawa H, Chihara T, Kondo K, Onogawa T, Nakamura S, Mori T, Tominaga M, Yabuuchi Y. OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist. Science. 1991 Apr 26;252(5005):572–574. [PubMed]
  • Imaizumi T, Harada S, Hirooka Y, Masaki H, Momohara M, Takeshita A. Effects of OPC-21268, an orally effective vasopressin V1 receptor antagonist in humans. Hypertension. 1992 Jul;20(1):54–58. [PubMed]
  • Guillon G, Balestre MN, Roberts JM, Bottari SP. Oxytocin and vasopressin: distinct receptors in myometrium. J Clin Endocrinol Metab. 1987 Jun;64(6):1129–1135. [PubMed]
  • Tence M, Guillon G, Bottari S, Jard S. Labelling of vasopressin and oxytocin receptors from the human uterus. Eur J Pharmacol. 1990 Dec 4;191(3):427–436. [PubMed]
  • Pettibone DJ, Kishel MT, Woyden CJ, Clineschmidt BV, Bock MG, Freidinger RM, Veber DF, Williams PD. Radioligand binding studies reveal marked species differences in the vasopressin V1 receptor of rat, rhesus and human tissues. Life Sci. 1992;50(25):1953–1958. [PubMed]
  • Guillon G, Butlen D, Cantau B, Barth T, Jard S. Kinetic and pharmacological characterization of vasopressin membrane receptors from human kidney medulla: relation to adenylate cyclase activation. Eur J Pharmacol. 1982 Dec 3;85(3-4):291–304. [PubMed]
  • Schmidt A, Audigier S, Barberis C, Jard S, Manning M, Kolodziejczyk AS, Sawyer WH. A radioiodinated linear vasopressin antagonist: a ligand with high affinity and specificity for V1a receptors. FEBS Lett. 1991 Apr 22;282(1):77–81. [PubMed]
  • Vittet D, Rondot A, Cantau B, Launay JM, Chevillard C. Nature and properties of human platelet vasopressin receptors. Biochem J. 1986 Feb 1;233(3):631–636. [PMC free article] [PubMed]
  • Stassen FL, Erickson RW, Huffman WF, Stefankiewicz J, Sulat L, Wiebelhaus VD. Molecular mechanisms of novel antidiuretic antagonists: analysis of the effects on vasopressin binding and adenylate cyclase activation in animal and human kidney. J Pharmacol Exp Ther. 1982 Oct;223(1):50–54. [PubMed]
  • Prpić V, Green KC, Blackmore PF, Exton JH. Vasopressin-, angiotensin II-, and alpha 1-adrenergic-induced inhibition of Ca2+ transport by rat liver plasma membrane vesicles. J Biol Chem. 1984 Feb 10;259(3):1382–1385. [PubMed]
  • Crause P, Fahrenholz F. Affinities of reactive vasopressin analogues for bovine antidiuretic receptor. Mol Cell Endocrinol. 1982 Nov-Dec;28(3):529–541. [PubMed]
  • Granger I, Serradeil-le Gal C, Augereau JM, Gleye J. Benzophenanthridine alkaloids isolated from Eschscholtzia californica cell suspension cultures interact with vasopressin (V1) receptors. Planta Med. 1992 Feb;58(1):35–38. [PubMed]
  • Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. [PubMed]
  • Munson PJ, Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. [PubMed]
  • BORN GV, CROSS MJ. THE AGGREGATION OF BLOOD PLATELETS. J Physiol. 1963 Aug;168:178–195. [PMC free article] [PubMed]
  • VAN ROSSUM JM. Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther. 1963;143:299–330. [PubMed]
  • ARUNLAKSHANA O, SCHILD HO. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. [PMC free article] [PubMed]
  • Barlow R, Blake JF. Hill coefficients and the logistic equation. Trends Pharmacol Sci. 1989 Nov;10(11):440–441. [PubMed]
  • Takemori AE, Hayashi G, Smits SE. Studies on the quantitative antagonism of analgesics by naloxone and diprenorphine. Eur J Pharmacol. 1972 Oct;20(1):85–92. [PubMed]
  • Howl J, Ismail T, Strain AJ, Kirk CJ, Anderson D, Wheatley M. Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function. Biochem J. 1991 May 15;276(Pt 1):189–195. [PMC free article] [PubMed]
  • Guillon G, Gallo-Payet N. Specific vasopressin binding to rat adrenal glomerulosa cells. Relationship to inositol lipid breakdown. Biochem J. 1986 Apr 1;235(1):209–214. [PMC free article] [PubMed]
  • Advenier C, Rouissi N, Nguyen QT, Emonds-Alt X, Breliere JC, Neliat G, Naline E, Regoli D. Neurokinin A (NK2) receptor revisited with SR 48968, a potent non-peptide antagonist. Biochem Biophys Res Commun. 1992 May 15;184(3):1418–1424. [PubMed]
  • Dudley DT, Panek RL, Major TC, Lu GH, Bruns RF, Klinkefus BA, Hodges JC, Weishaar RE. Subclasses of angiotensin II binding sites and their functional significance. Mol Pharmacol. 1990 Sep;38(3):370–377. [PubMed]
  • Altura BM. Dose-response relationships for arginine vasopressin and synthetic analogs on three types of rat blood vessels: possible evidence for regional differences in vasopressin receptor sites within a mammal. J Pharmacol Exp Ther. 1975 May;193(2):413–423. [PubMed]
  • Liard JF. Cardiovascular effects of vasopressin: some recent aspects. J Cardiovasc Pharmacol. 1986;8 (Suppl 7):S61–S65. [PubMed]
  • Thibonnier M, Roberts JM. Characterization of human platelet vasopressin receptors. J Clin Invest. 1985 Nov;76(5):1857–1864. [PMC free article] [PubMed]

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