Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1979 Jun;76(6):2566–2570. doi: 10.1073/pnas.76.6.2566

Synthesis and biological properties of pinane-thromboxane A2, a selective inhibitor of coronary artery constriction, platelet aggregation, and thromboxane formation.

K C Nicolaou, R L Magolda, J B Smith, D Aharony, E F Smith, A M Lefer
PMCID: PMC383648  PMID: 288046

Abstract

Pinane-thromboxane A2 (PTA2, [1alpha,2 beta(Z),-3 alpha (1E,3R*),5 alpha]-7-(3-(3-hydroxy-1-octenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)-5-heptenoic acid) has been synthesized and tested for biological activity in systems responsive to thromboxane A2, stable prostaglandin endoperoxide (PGH2) analogs, and prostatacyclin (PGI2). At low concentrations, PTA2 inhibited cat coronary artery constriction induced by stable prostaglandin endoperoxide analogs, and it stabilized liver lysosomes. At slightly higher concentrations, it inhibited platelet aggregation. At still higher concentrations, PTA2 inhibited thromboxane synthetase, but it had no effect on prostacyclin synthetase. The analog also had no effect on the inhibition of platelet aggregation by PGI2 or prostaglandin D2. It is suggested that PTA2 has a suitable biochemical profile for use as an antithrombotic agent.

Full text

PDF
2566

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bills T. K., Smith J. B., Silver M. J. Metabolism of [14C]arachidonic acid by human platelets. Biochim Biophys Acta. 1976 Feb 23;424(2):303–314. doi: 10.1016/0005-2760(76)90198-3. [DOI] [PubMed] [Google Scholar]
  2. Corey E. J., Nicolaou K. C., Machida Y., Malmsten C. L., Samuelsson B. Synthesis and biological properties of a 9,11-azo-prostanoid: highly active biochemical mimic of prostaglandin endoperoxides. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3355–3358. doi: 10.1073/pnas.72.9.3355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cottee F., Flower R. J., Moncada S., Salmon J. A., Vane J. R. Synthesis of 6-keto-PGF1alpha by ram seminal vesicle microsomes. Prostaglandins. 1977 Sep;14(3):413–423. doi: 10.1016/0090-6980(77)90257-x. [DOI] [PubMed] [Google Scholar]
  4. Ellis E. F., Oelz O., Roberts L. J., 2nd, Payne N. A., Sweetman B. J., Nies A. S., Oates J. A. Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2. Science. 1976 Sep 17;193(4258):1135–1137. doi: 10.1126/science.959827. [DOI] [PubMed] [Google Scholar]
  5. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  6. Fitzpatrick F. A., Bundy G. L., Gorman R. R., Honohan T. 9,11-epoxyiminoprosta-5,13-dienoic acid is a thromboxane A2 antagonist in human platelets. Nature. 1978 Oct 26;275(5682):764–766. doi: 10.1038/275764a0. [DOI] [PubMed] [Google Scholar]
  7. Gorman R. R., Bundy G. L., Peterson D. C., Sun F. F., Miller O. V., Fitzpatrick F. A. Inhibition of human platelet thromboxane synthetase by 9,11-azoprosta-5,13-dienoic acid. Proc Natl Acad Sci U S A. 1977 Sep;74(9):4007–4011. doi: 10.1073/pnas.74.9.4007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hamberg M., Svensson J., Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U S A. 1975 Aug;72(8):2994–2998. doi: 10.1073/pnas.72.8.2994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hamberg M., Svensson J., Wakabayashi T., Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc Natl Acad Sci U S A. 1974 Feb;71(2):345–349. doi: 10.1073/pnas.71.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Malmsten C. Some biological effects of prostaglandin endoperoxide analogs. Life Sci. 1976 Jan 15;18(2):169–176. doi: 10.1016/0024-3205(76)90021-7. [DOI] [PubMed] [Google Scholar]
  11. Miyake H., Iguich S., Itoh H., Hayashi M. Simple synthesis of methyl (5Z,9alpha,11alpha, 13E,15S)-9,11-epidithio-15-hydroxyprosta-5,13-dienoate, endodisulfide analogue of PGH2. J Am Chem Soc. 1977 May 11;99(10):3536–3537. doi: 10.1021/ja00452a075. [DOI] [PubMed] [Google Scholar]
  12. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  13. Needleman P., Bryan B., Wyche A., Bronson S. D., Eakins K., Ferrendelli J. A., Minkes M. Thromboxane synthetase inhibitors as pharmacological tools: differential biochemical and biological effects on platelet suspensions. Prostaglandins. 1977 Nov;14(5):897–907. doi: 10.1016/0090-6980(77)90306-9. [DOI] [PubMed] [Google Scholar]
  14. Needleman P., Minkes M., Raz A. Thromboxanes: selective biosynthesis and distinct biological properties. Science. 1976 Jul 9;193(4248):163–165. doi: 10.1126/science.945611. [DOI] [PubMed] [Google Scholar]
  15. Nicolaou K. C., Gasic G. P., Barnette W. E. Synthesis and biological properties of prostaglandin endoperoxides, thromboxanes and prostacyclins. Angew Chem Int Ed Engl. 1978 May;17(5):293–312. doi: 10.1002/anie.197802933. [DOI] [PubMed] [Google Scholar]
  16. Nugteren D. H., Hazelhof E. Isolation and properties of intermediates in prostaglandin biosynthesis. Biochim Biophys Acta. 1973 Dec 20;326(3):448–461. doi: 10.1016/0005-2760(73)90145-8. [DOI] [PubMed] [Google Scholar]
  17. Ogletree M. L., Smith J. B., Lefer A. M. Actions of prostaglandins on isolated perfused cat coronary arteries. Am J Physiol. 1978 Oct;235(4):H400–H406. doi: 10.1152/ajpheart.1978.235.4.H400. [DOI] [PubMed] [Google Scholar]
  18. Okuma M., Yoshimoto T., Yamamoto S. Human platelet aggregation induced by prostaglandin endodisulfide. Prostaglandins. 1977 Nov;14(5):891–896. doi: 10.1016/0090-6980(77)90305-7. [DOI] [PubMed] [Google Scholar]
  19. Smith J. B., Ingerman C., Kocsis J. J., Silver M. J. Formation of prostaglandins during the aggregation of human blood platelets. J Clin Invest. 1973 Apr;52(4):965–969. doi: 10.1172/JCI107262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sun F. F., Chapman J. P., McGuire J. C. Metabolism of prostaglandin endoperoxide in animal tissues. Prostaglandins. 1977;14(6):1055–1074. doi: 10.1016/0090-6980(77)90285-4. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES