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Chemical Compound Review

U-46619     (Z)-7-[(1R,4R,5S,6S)-5- [(E,3S)-3...

Synonyms: CHEMBL521784, BSPBio_001534, SureCN12272421, CHEBI:583940, BML1-G04, ...
 
 
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Disease relevance of U-46619

 

High impact information on U-46619

 

Chemical compound and disease context of U-46619

 

Biological context of U-46619

  • Multiple dosing with GR32191, 17.5 mg (equivalent to 0.25 mg/kg for a 70 kg subject), three times daily (three subjects) or every 12 hours (six subjects), resulted in a cumulative inhibitory effect on U-46619 platelet aggregation in the apparent absence of a build-up of plasma concentrations of GR32191 [16].
  • During U46619 infusion pulmonary vasodilation was maintained up to 1 hour without tolerance [17].
  • Bradykinin and its analogues did not inhibit ADP-, collagen-, U46619-, or SFLLRN-induced platelet activation or the ability of alpha-thrombin to cleave chromogenic substrates, clot fibrinogen, or block alpha-thrombin binding to platelets [18].
  • These findings were paralleled by a 52+/-5% (P<.05) increase in cell number at 48 hours after addition of both mitogens as compared with 24+/-5% with thrombin alone and no change with U 46619 alone [19].
  • Pretreatment of SMC with thrombin for 4 hours markedly increased U 46619-induced mitogen-activated protein kinase activity, indicating thrombin-induced upregulation of functional thromboxane receptors in SMC [19].
 

Anatomical context of U-46619

  • GTPase activity (a function of alpha-subunit) in platelet membranes was normal in resting state but was diminished compared with normal subjects on stimulation with thrombin, platelet-activating factor, or the thromboxane A2 analog U46619 [20].
  • Porcine coronary arteries were stimulated with either KCl or U46619 [21].
  • Vascular responses to the thromboxane analogue U46619 were measured in four separate experimental protocols: 1) The vascular responses were measured in the presence and absence of intact endothelium to examine the role of endothelium-derived vasodilators [22].
  • Addition of U46619 to confluent fura 2-loaded endothelial cells caused a concentration-dependent rise in intracellular [Ca2+]i, with agonist concentrations of 300 nM producing a maximal [Ca2+]i rise [23].
  • These results suggest that the effects of U46619 in increasing vascular smooth muscle cell calcium efflux are receptor mediated [24].
 

Associations of U-46619 with other chemical compounds

 

Gene context of U-46619

  • U46619-mediated ERK activation was inhibited by the TP antagonist [1S-[1alpha,2beta-(5Z)-3beta,4alpha-]]-7-[3-[[2-(phenylamino)carbonyl]hydrazine] methyl]-7-oxabicyclo[-2,2,1-]hept-2yl]-5-heptenoic acid (SQ29,548), and by the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD 98059) [30].
  • Previous observations had demonstrated a role for bFGF in the expression of U46619 actions on protein synthesis [31].
  • To determine which G-proteins are implicated in the U46619-induced IL-6 synthesis, the interfering mutants of Galpha(q), Galpha12, or Galpha13 by were overexpressed in 1321N1 cells adenoviral approach [32].
  • U46619 increased DNA and protein synthesis, cell number, IP formation, [Ca2+]i, and MAPK and MAPKK activities, with EC50 values close to its Kd value for the low-affinity binding site in VSMCs from SHR [33].
  • Our data show that NKB is a dilator of the fetal vasculature, causing a maximal 25.1 +/- 4.5% (mean +/- SEM; n = 5) decrease in fetal-side arterial hydrostatic pressure (5- microM NKB bolus; effective concentration in the circulation, 1.89 nM) after preconstriction with U-46619 [34].
 

Analytical, diagnostic and therapeutic context of U-46619

  • Inhaled nitric oxide (150 ppm for 3 minutes) reduced pulmonary perfusion pressure, elevated by a continuous infusion of U46619, by 35 +/- 7% (mean +/- SEM, n = 5) [35].
  • The vasoconstrictive response to U46619 was enhanced for the first 30 minutes of reperfusion and returned to normal within 60 minutes [36].
  • Intracoronary infusion of U46619 (0.01-1.0 microgram/min) produced a dose-dependent constriction of LAD [22].
  • The relaxing activity of the effluent was monitored in canine coronary artery rings without endothelium (bioassay tissue) half-maximally contracted with U46619 [37].
  • As shown by flow cytometry, a tail population that had a minimal increase in F-actin upon stimulation with ADP or U46619 also contained the platelets with the least forward and right angle light scattering, which are functions of platelet size and shape [38].

References

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  16. Preliminary assessment of a novel thromboxane A2 receptor-blocking drug, GR32191, in healthy subjects. Thomas, M., Lumley, P. Circulation (1990) [Pubmed]
  17. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Frostell, C., Fratacci, M.D., Wain, J.C., Jones, R., Zapol, W.M. Circulation (1991) [Pubmed]
  18. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation. Hasan, A.A., Amenta, S., Schmaier, A.H. Circulation (1996) [Pubmed]
  19. Thrombin-induced mitogenesis in coronary artery smooth muscle cells is potentiated by thromboxane A2 and involves upregulation of thromboxane receptor mRNA. Zucker, T.P., Bönisch, D., Muck, S., Weber, A.A., Bretschneider, E., Glusa, E., Schrör, K. Circulation (1998) [Pubmed]
  20. Platelet signal transduction defect with Galpha subunit dysfunction and diminished Galphaq in a patient with abnormal platelet responses. Gabbeta, J., Yang, X., Kowalska, M.A., Sun, L., Dhanasekaran, N., Rao, A.K. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
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  23. Identification of functional PGH2/TxA2 receptors on human endothelial cells. Kent, K.C., Collins, L.J., Schwerin, F.T., Raychowdhury, M.K., Ware, J.A. Circ. Res. (1993) [Pubmed]
  24. Cultured human vascular smooth muscle cells with functional thromboxane A2 receptors: measurement of U46619-induced 45calcium efflux. Dorn, G.W., Sens, D., Chaikhouni, A., Mais, D., Halushka, P.V. Circ. Res. (1987) [Pubmed]
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  27. Combined ADP and thromboxane A2 antagonism prevents cyclic flow variations in stenosed and endothelium-injured arteries in nonhuman primates. Yao, S.K., McNatt, J., Cui, K., Anderson, H.V., Maffrand, J.P., Buja, L.M., Willerson, J.T. Circulation (1993) [Pubmed]
  28. Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Ge, T., Hughes, H., Junquero, D.C., Wu, K.K., Vanhoutte, P.M., Boulanger, C.M. Circ. Res. (1995) [Pubmed]
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  31. Thromboxane/prostaglandin endoperoxide-induced hypertrophy of rat vascular smooth muscle cells is signaled by protein kinase C-dependent increases in transforming growth factor-beta. Craven, P.A., Studer, R.K., DeRubertis, F.R. Hypertension (1996) [Pubmed]
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  37. Endothelium-derived relaxing factor released from canine femoral artery by acetylcholine cannot be identified as free nitric oxide by electron paramagnetic resonance spectroscopy. Greenberg, S.S., Wilcox, D.E., Rubanyi, G.M. Circ. Res. (1990) [Pubmed]
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