Advertisement

Screening for Inhibitors of Prostaglandin and Thromboxane Biosynthesis

  • Ryszard J. Gryglewski
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 13)

Abstract

Many in vitro methods have been employed to predict the anti-inflammatory potency of newly synthetized compounds. These methods are essentially based on the interaction of drugs with enzymic and non-enzymic proteins. Anti-inflammatory drugs are supposed to protect albumin against heat denaturation (Mizushima, 1964), to displace marker compounds from binding sites of albumin (Skidmore and Whitehouse, 1965), to induce fibrinolysis in plasma clots (Gryglewski, 1966), to accelerate disulfide interchange reaction between serum protein and sulfhydryl reagents (Gerber et al., 1967), to stabilize erythrocyte (Brown et al., 1967) and lysosomal (Miller and Smith, 1966) membranes as well as to inhibit a wide range of enzymes including uncoupling of oxydative phosphorylation (Whitehouse and Haslam, 1962) and inhibition of cyclic-AMP phosphodiesterase (Weinryb et al., 1972; Moffat et al., 1972).

Keywords

Arachidonic Acid Platelet Rich Plasma Mefenamic Acid Biosynthesis Inhibitor Induce Platelet Aggregation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Brodie, B.B., and Hogben, C.A.M., 1957, Some physico-chemical factors in drug action, J. Pharm. Pharmacol. 9: 345–380.PubMedCrossRefGoogle Scholar
  2. Brown, J.H., Mackey, H.K., and Rigillo, D.A., 1967, A novel in vitro assay for anti-inflammatory agents based on stabilization of erythrocytes, Proc.Soc. exp. Biol. Med. 125: 837–843.PubMedGoogle Scholar
  3. Bunting, S., Moncada, S., Needleman, P., and Vane, J.R., 1976a, Prostaglandin endoperoxides and thromboxane generating systems and their selective inhibition, Br. J. Pharmac. 56: 334P–345P.Google Scholar
  4. Bunting, S., Moncada, S., and Vane, J.R., The effects of prostaglandin endoperoxides and thromboxane A2 on strips of rabbit coeliac artery and certain other smooth muscle preparations, Proc. Br. Pharmacol. Soc. 1–2 April 1976b, p.48.Google Scholar
  5. Caprino, L., Borelli, F., and Falchetti, R., 1973b, Effect of 4,5-diphenyl-2-bis-(2-hydroxyethyl)-ami-noxazol (Ditazol) on platelet aggregation, adhesiv-ness and bleeding time, Arzneimittel Forsch. 23; 1277–1283.Google Scholar
  6. Chignell, C.F., 1969, Optical studies of drug-protein complexesm III. Interaction of flufenamic acid and other N-aryl-anthranilates with serum albumin. Molec. Pharmac. 5: 455–462.Google Scholar
  7. Chignell, C.F., 1971, Physical methods for studing drug-protein binding, in: Handb. Exp. Pharm. 28/1, Concepts in Biochemical Pharmacology, (B. Brodie and J.R. Gilette, eds.), pp. 187–212, Springer-Verlag, Berlin, Heidelberg, New York.Google Scholar
  8. Constantine, D.W., and Purcell, I.M., 1973, Inhibition of platelet aggregation and of experimental thrombosis by sudoxicam. J. Pharmacol. Exper. Ther. 187: 653–665.Google Scholar
  9. Daniel, E., Weber, C., 1966, Cooperative effects in binding by bovine seru.m albumin. The binding of 1-anilino-8-naphthalene sulphonate. Fluorimetrie titrations. Biochemistry 5: 1893–1907.Google Scholar
  10. Darska, J., 1976, Comparison of radiochemical and biological assays of prostaglandin synthetase activity in bovine seminal vesicle microsomes. PhD thesis. Copernicus Academy of Medicine in Cracow.Google Scholar
  11. Deby, C., Descamps, M., Binon, F., and Bacq, Z.M., 1971, Inhibition de la biosynthése in vitro de la Prostaglandine E2 par des substances anti-inflammatoires. C.R. Soc. Biol. 165: 2465–2468.Google Scholar
  12. De Clerck, F., Vermylen, J., and Reneman, R., 1975, Effects of suprofen, an inhibitor of prostaglandin biosynthesis, on platelet function, plasma coagulation and fibrynolysis* I. In vitro experiments. Arch. int. Pharmacodyn. 216: 263–279.PubMedGoogle Scholar
  13. Dembińska-Kieć, A., Żmuda, A., and Krupińska, J., 1976, Inhibition of prostaglandin synthetase by aspirin--like drugs in different microsomal preparation, in: Advances in Prostaglandin and Thromboxane Research, Vol.1 (B. Samuelsson and R. Paoletti, eds.), p.99, Raven Press New York.Google Scholar
  14. Ferreira, S.H., Moncada, S., and Vane, J.R., 1971, Indomethacin and aspirin abolish prostaglandin release from the spleen. Nature New Biol. 231: 237–239.PubMedCrossRefGoogle Scholar
  15. Fjalland, B., 1974, Inhibition by non-steroidal antiinflammatory agents of the release of rabbit aorta contracting substance and prostaglandins from chopped guinea pig lungs. J.Pharm. Pharmacol. 26: 448–451.PubMedCrossRefGoogle Scholar
  16. Flanagan, M.T., and Ainworth, S., 1968, The binding of aromatic sulphonic acids to bovine serum albumin. Biochim. Biophys. Acta 168: 16–26.PubMedGoogle Scholar
  17. Flower, R.J., 1974, Drugs which inhibit prostaglandin biosynthesis. Pharmac. Rev. 26: 33–67.Google Scholar
  18. Flower, R.J., Blackwell, G.J., and Parsons, M.F., 1975, Mechanism of collagen induced platelet aggregation. Abstr. VIth Internat. Congress Pharmac. p.292, Helsinki.Google Scholar
  19. Flower, R.J., Cheung, H.S., and Cushman, D.W., 1973, Quantitative determination of prostaglandins and malonyldialdehyde formed by arachidonate oxygenase system in bovine seminal vesicles. Prostaglandins 4: 325–341.PubMedCrossRefGoogle Scholar
  20. Flower, R.J., Gryglewski, R., Herbaczyńska-Cedro, K., and Vane, J.R., 1972, The effect of anti-inflammatory drugs on prostaglandin biosynthesis. Nature, New Biol. 238: 104–106.Google Scholar
  21. Flower, R.J., and Vane, J.R., 1972, Inhibition of prostaglandin synthetase in brain explains the antipyretic activity of paracetamol (4-acetamidophenol). Nature 240: 410–411.PubMedCrossRefGoogle Scholar
  22. Gaut, Z.N., Baruth, H., Randall, L.J., Ashley, C., and Paulsrud, J.R., 1975, Stereometric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase. Prostaglandins 10,: 59–66.PubMedGoogle Scholar
  23. Gerber, D.A., Cohen, Nrn., and Giustra, R., 1967, The ability of nonsteroidal anti-inflammatory compounds to accelerate a disulfide interchange reaction of serum sulfhydryl groups and 5,5’-dithio-bis-(2-nitrobenzoic) acid. Biochem. Pharmac. 16: 115–120.CrossRefGoogle Scholar
  24. Gilmore, N., Vane, J.R., and Wyllie, J.H., 1968, Prostaglandins released by the spleen. Nature 218: 1135–1137.PubMedCrossRefGoogle Scholar
  25. Glenn, E.M., Rohloff, N., Bowman, B.J., and Lyster, S. C., 1973, The pharmacology of 2-(2-fluoro-4-biphe-nylyDpropionic acid (flurbiprofen) a potent nonsteroidal anti-inflammatory drug. Agents and Actions 3/4: 210–216.PubMedCrossRefGoogle Scholar
  26. Glenn, E.M., Wilks, J., and Bowman, B.D., 1972, Platelets, prostaglandins, red cells, sedimentation rates serum and tissues proteins and non-steroidal antiinflammatory drugs. Proc.Soc.Exp.Med. 141:879–886.Google Scholar
  27. Gryglewski, R., 1966, The fibrinolytic activity of antiinflammatory drugs. J.Pharm. Pharmac. 18: 474.CrossRefGoogle Scholar
  28. Gryglewski, R., 1974, Structure-activity relationships of some prostaglandin synthetase inhibitors, in: Prostaglandin Synthetase Inhibitors (H.J. Robinson and J.R. Vane, eds.), pp. 33–52, Raven Press, New York.Google Scholar
  29. Gryglewski, R.J., 1976, Steroid hormones, anti-inflammatory steroids and prostaglandins. Pharmacol. Res. Commun. 8: 337–348.Google Scholar
  30. Gryglewski, R.J., Ryznerski, Z., Gorczyca, M., and Krupińska, J., 1976a, Design of new prostaglandin synthetase inhibitors in a group of N-(2-carboxy-phenyl)phenoxyacetamides and their anti-inflammatory activity, in: Advances in Prostaglandin and Thromboxane Research, Vol. 1 (B. Samuelsson and R. Paoletti, eds.), pp. 117–120. Raven Press, New York.Google Scholar
  31. Gryglewski, R.J., Dembińska-Kieć, A., Grodzińska, L., and Panczenko, J., 1976b, Differential generation of substances with prostaglandin-like and thrombo-xane-like activities by guinea pig trachea and by lung strips, in:Lung cells in disease (A. Bouhuys, ed.), in press. Elseview Pub. Amsterdam.Google Scholar
  32. Gryglewski, R., and Vane, J.R., 1972a, The release of prostaglandins and rabbit aorta contracting substance (RCS) from rabbit spleen and its antagonism by anti-inflammatory drugs. Br.J. Pharmac. 45: 37–47.Google Scholar
  33. Gryglewski, R., and Vane, J.R., 1972b, The generation from arachidonic acid of rabbit aorta contracting substance (RCS) by microsomal enzyme preparation which also generates prostaglandins. Br.J.Pharmac. 45: 449–457.Google Scholar
  34. Ham, E.A., Cirillo, K.J., Zanetti, M., Shen, T.Y., and Kuehl, F.A., 1972, Studies on the mode of action of non-steroidal anti-inflammatory agents, in: Prostaglandins in cellular biology (P.W. Ramwell and B.B. Pharriss, eds.), pp. 345–352. Plenum Press, New York.Google Scholar
  35. Hamberg, M., 1972, Inhibition of prostaglandin synthesis in man. Biochem. Biophys. Res. Commun. 49: 720–726.PubMedCrossRefGoogle Scholar
  36. Hamberg, M., Svensson, J., and Samuelsson, B., 1975, Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Nat. Acad. Sci. USA, 72: 2994–2998.PubMedCrossRefGoogle Scholar
  37. Hamberg, M., Svensson, J., Wakabayashi, T., and Samuels-son, B., 1974, Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc.Nat. Acad. Sci. USA, 71 345–349.PubMedCrossRefGoogle Scholar
  38. Ho, P.P., and Esterman, M.A., 1974, Fenoprofen: inhibition of prostaglandin synthesis. Prostaglandins, 6: 107–113.CrossRefGoogle Scholar
  39. Horodniak, J.W., Julius, M., Zarembo, J.E., and Bender, D., 1974, Inhibitory effects of aspirin and indo-methacin on the biosynthesis of PGE2 and PGF Biochem. Biophys. Res. Commun. 57: 539–5457CrossRefGoogle Scholar
  40. Ku, E.C., and Wasvary, J.M., 1975, Inhibition of prostaglandin synthetase by pirprofen. Studies with sheep seminal vesicle enzyme. Biochim. Biophys..Acta 384: 360–368.PubMedGoogle Scholar
  41. Lands, W.E.M., Cook, H.W., and Rome, L.H., 1975, Prostaglandin biosynthesis: consequences of oxygenase mechanism upon in vitro assays of drug effectiveness. Abstr. Int. Conference on Prostaglandins, p.3, Florence.Google Scholar
  42. Lands, W., Lee, R., and Smith, W., 1971, Factors regulating the biosynthesis of various prostaglandins. Ann. N.Y. Acad. Sci. 180: 107–122.PubMedCrossRefGoogle Scholar
  43. Levine, L., 1972, Prostaglandin production by mouse fibrosarcoma cells in culture: Inhibition by indo-methacin and aspirin. Biochem. Biophys. Re. Commun. 47: 888–896.CrossRefGoogle Scholar
  44. Lewis, G.P., and Piper, P.J., 1975, Inhibition of release of prostaglandins as an explanation of some of the actions of anti-inflammatory corticosteroids. Nature 254: 308–311.PubMedCrossRefGoogle Scholar
  45. Malmsten, C., Hamberg, M., Svensson, J., and Samuelsson, B., 1975, Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency. Proc. Nat. Acad. Sci. USA, 72:1446–1450.PubMedCrossRefGoogle Scholar
  46. Meyer, M.C., and Guttman, D.E., 1968, The binding of drugs by plasma proteins. J. Pharm. Sci. 57: 895–917.PubMedCrossRefGoogle Scholar
  47. Miller, W.S., and Smith, J.G., 1966, Effect of acetyl-salicylic acid on lysosomes. Proc. Soc. Exp. Biol. Med. 122: 634–636.PubMedGoogle Scholar
  48. Mizushima, Y., 1964, Inhibition of protein denaturation by anti-rheumatic or antiphlogistic agents. Arch. Int. Pharmacodyn. 149: 1–7.PubMedGoogle Scholar
  49. Mizushima, Y., Ishi, Y., and Masumoto, S., 1975, Physico-chemical properties of potent non-steroidal anti-inflammatory drugs. Biochem. Pharmacol. 24: 1589–1592.PubMedCrossRefGoogle Scholar
  50. Moffat, A.C., Patterson, D.A., Curry, A.S., and Gwen, P., 1972, Inhibition in vitro of cyclic 3’,5’--nucleotide phosphodiesterase activity by drugs. Eur. J. Toxicol. 5: 160–162.PubMedGoogle Scholar
  51. Mustard, J.F., and Packham, M.A., 1975, Platelets, thrombosis and drugs. Drugs 9: 19–76.PubMedCrossRefGoogle Scholar
  52. Needleman, P., Moncada, S., Bunting, S., Vane, J.R., Hamberg, M., and Samuelsson, B., 1976a, Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endo-peroxides. Nature 261: 558–560.CrossRefGoogle Scholar
  53. Needleman, P., Minkes, M., and Raz, A., 1976b. Thromboxanes: Selective biosynthesis and distinct biological properties. Science 193: 163–165.PubMedCrossRefGoogle Scholar
  54. O’Brien, J.R., 1968, Effect of anti-inflammatory agents on platelets. Lancet 1: 894–895.PubMedCrossRefGoogle Scholar
  55. Patrono, C., Ciabattoni, G., Greco, F., and Grossi-Belloni, D., 1976, Comparative evaluation of the inhibitory effects of aspirin-like drugs on prostaglandin production by human platelets and synovial tissue, in: Advances in Prostaglandin and Thromboxane Research, Vol. 1 (B. Samuelsson and R. Paoletti, eds.), pp. 125–131, Raven Press, New York.Google Scholar
  56. Piper, P.J., and Vane, J.R., 1969, Release of additional factors in anaphylaxis and its antagonism by antiinflammatory drugs. Nature 233: 29–35.CrossRefGoogle Scholar
  57. Robak, J., Dembińska-Kieć, A., and Gryglewski, R., 1975, The influence of saturated fatty acids on prostaglandin synthetase activity. Biochem. Pharmac. 24: 2057–2060.CrossRefGoogle Scholar
  58. Roth, G.J., Stanford, N., and Majerus, P.W., 1975, Acetylation of prostaglandin synthetase by aspirin. Proc.Nat. Acad. Sci., USA, 72: 3073–3076CrossRefGoogle Scholar
  59. Samuelsson, B., Granström, E., and Hamberg, M., 1967, On the mechanism of biosynthesis of prostaglandins, in: Nobel Symposium 2 Prostaglandins (S. Bergstrom and B. Samuelsson, eds.), pp.31–44, Almqvist and Wiksell, Stockholm.Google Scholar
  60. Samuelsson, B., Hamberg, M., Svensson, J., and Malmsten, C., 1975, The role of prostaglandin endoperoxides in human platelets. Abstr. Vlth Congress Pharmac. p. 480, Helsinki.Google Scholar
  61. Scatchard, G., 1949, The attractions of proteins for small molecules and ions. Ann. N.Y. Acad. Sci. 51: 660–672.CrossRefGoogle Scholar
  62. Schaeffer, H.J., 1971, Factors in the design of reversible and irreversible enzyme inhibitors, in: Drug Design, Vol. II (E.J. Ariens, ed.), pp. 129–160, Academic Press, New York, London.Google Scholar
  63. Settle, W., Hegeman, S., and Featherstone, R.M., 1971, The nature of drug-protein interaction, in: Handb. Exp. Pharm. 28/1, Concepts in Biochemical Pharmacology, (B. Brodie and J.R. Gilette, eds.), Springer-Verlag, Berlin, Heidelberg, New York, pp. 175–186.Google Scholar
  64. Shen, T.Y., Ham, E.A., Cirillo, V.J., and Zanetti, M., 1974, Structure-activity relationship of certain prostaglandin synthetase inhibitors, in: Prostaglandin Synthetase Inhibitors (H.J. Robinson and J.R. Vane, eds.), pp. 19–31. Raven Press, New York.Google Scholar
  65. Sih, C.J., and Takeguchi, C.A., 1973, Biosynthesis, in: The Prostaglandins, Vol. I. (P.W. Ramwell, ed.), pp. 83–100, Plenum Press, New York, London.Google Scholar
  66. Silver, M.J., Smith, J.B., Ingerman, C., and Kocsis, J. J., 1973, Arachidonic acid-induced human platelet aggregation and prostaglandin formation. Prostaglandins 4: 863–875.PubMedCrossRefGoogle Scholar
  67. Skidmore, I.F., Whitehouse, M.W., 1965, Effect of-nonsteroidal anti-inflammatory drugs on aldehyde binding to plasma albumen: a novel in vitro assay for potential anti-inflammatory activity. J. Pharm. Pharmac. 17: 671–673.CrossRefGoogle Scholar
  68. Skidmore, I.F., and Whitehouse, M.W., 1966, Concerning the regulation of some diverse biochemical reactions underlying the inflammatory response by salicylic acid, phenylbutazone and other acidic antirheumatic drugs. J. Pharm. Pharmac. 18: 558–560.CrossRefGoogle Scholar
  69. Smith, W.L., and Lands, W.E.M., 1971, Stimulation and blockade of prostaglandin biosynthesis. J. Biol. Chem. 246: 6700–6702.PubMedGoogle Scholar
  70. Smith, J.B., and Willis, A.L., 1971, Aspirin selectively inhibits prostaglandin production in human platelets. Nature New Biol. 231: 235–237.PubMedGoogle Scholar
  71. Svensson, J., Hamberg, M., and Samuelsson, B., 1975, Prostaglandin endoperoxides IX. Characterization of rabbit aorta contracting substance (RCS) from guinea pig lung and human platelets. Acta Physiol. Scand. 94: 222–228.PubMedCrossRefGoogle Scholar
  72. Takeguchi, C., Kohono, E., Sih, C.J., 1971, Mechanism of prostaglandin biosynthesis. I. Characterization and assay of bovine prostaglandin synthetase. Biochemistry 10: 2372–2376.PubMedCrossRefGoogle Scholar
  73. Takeguchi, G., and Sih, C.J., 1972, A rapid spectrophotometry assay for prostaglandin synthetase: Application to the study of non-steroidal antiinflammatory agents. Prostaglandins 2: 169–184.PubMedCrossRefGoogle Scholar
  74. Tomlinson, R.V., Ringold, H.D., Quershi, M.C., and Forchielli, E., 1972, Relationship between inhibition of prostaglandin synthesis and drug efficacy: Support for the current theory on mode of action of aspirinlike drugs. Biochem. Biophys. Res. Commun. 46: 552–559.PubMedCrossRefGoogle Scholar
  75. Vane, D.R., 1957, A sensitive method for the assay of 5-hydroxytryptamine. Br. D. Pharmac. Chemother. 12: 344–349.Google Scholar
  76. Vane, D.R., 1964, The use of isolated organs for detecting active substances in the circulating blood. Br. D. Pharmac. Chemother. 23: 360–373.Google Scholar
  77. Vane, D.R., 1971, Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 231: 232–235.PubMedGoogle Scholar
  78. Vane, D.R., 1972a, Prostaglandins in inflammation, in: Inflammation, mechanisms and control (I.H. Lepow, and P.A. Ward, eds.), pp. 261–279, Academic Press, New York, London.Google Scholar
  79. Vane, D.R., 1972b, Prostaglandins and aspirin-like drugs. Hosp. Pract. 7: 61–71.Google Scholar
  80. Vargaftig, B.B., and Dao Hai, N., 1971, Release of vasoactive substances from guinea-pig lungs by slow reacting substance C and arachidonic acid. Pharmacology 6: 99–108.PubMedCrossRefGoogle Scholar
  81. Vargaftig, B.B., and Zirinis, P., 1973, Arachidonic acid induced platelet aggregation is accompanied by release of potential inflammatory mediators distinct from PGE2 and PGF2. Nature New Biol. 244: 114–116.PubMedGoogle Scholar
  82. Weinryb, I., Chasin, M., Free, C.A., Harris, D.M., Goldenberg, H., Michel, I.M., Raik, V.S., Phillips, M., Samamiego, S., and Hess, S., 1972, Effects of therapeutic agents on cyclic AMP metabolism in vitro: J. Pharm. Sci. 61: 1556–1567.PubMedCrossRefGoogle Scholar
  83. Weiss, H. J., Aledort, L.M., and Kochwa, S., 1968, The effect of salicylates on the hemostatic properties of platelets in man. O. Clin. Invest. 47: 2169–2180.CrossRefGoogle Scholar
  84. Whitehouse, M.W., and Haslam, D.M., 1962, Äbility of some antirheumatic drugs to uncouple oxydative phosphorylation. Nature 196: 1323–1324.PubMedCrossRefGoogle Scholar
  85. Whitehouse, M.W., Kippen, I., and Klinenberg, J.R., 1971, Biochemical properties of anti-inflammatory drugs — XII. Inhibition of urate binding to human albumin by salicylate and phenylbutazone analogues and some novel anti-inflammatory drugs. Biochem. Pharmac. 20: 3309–3320.CrossRefGoogle Scholar
  86. Wiethold, G., Hellenbrecht, D., Lemmer, B., and Palm, D., 1973, Membrane effects of beta-adrenorgic blocking agents: investigations with the fluorescence probe l-anilino-8-naphthalene sulphonate (ANS) and antihemolytic activities. Biochem. Pharmacol. 22: 1437–1449.PubMedCrossRefGoogle Scholar
  87. Willis, A.L., 1974, An enzymic mechanism for the antithrombotic and antihemostatic actions of aspirin. Science 183: 325–327.PubMedCrossRefGoogle Scholar
  88. Willis, A.L., and Kuhn, D.C., 1973, A new potential mediator of arterial thrombosis whose biosynthesis is inhibited by aspirin. Prostaglandins 4: 127–129.PubMedCrossRefGoogle Scholar
  89. Wiseman, E.H., Mcllhenny, H.M., and Bettis, D.W., 1975, Flumizole, a new nonsteroidal anti-inflammatory agent. O. Pharm. Sci. 64: 1469–1475.CrossRefGoogle Scholar
  90. Zaroślinski, O.F., Keresztes-Nagy, S., Mass, R.F., and Oester, Y.T., 1974, Effect of temperature on the binding of salicylate by human serum albumin. Biochem. Pharmac. 23: 1767–1776.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Ryszard J. Gryglewski
    • 1
  1. 1.Department of PharmacologyCopernicus Academy of Medicine in CracowCracowPoland

Personalised recommendations