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Molecular Pharmacology

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Research ArticleArticle

Analogues of Arachidonic Acid Used To Evaluate Structural Determinants of Prostaglandin Receptor and Enzyme Specificities

LOUISE E. LEDUC, ANGELA A. WYCHE, HOWARD SPRECHER, S. K. SANKARAPPE and PHILIP NEEDLEMAN
Molecular Pharmacology March 1981, 19 (2) 242-247;
LOUISE E. LEDUC
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Physiological Chemistry, Ohio State University, Columbus, Ohio 43210
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ANGELA A. WYCHE
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Physiological Chemistry, Ohio State University, Columbus, Ohio 43210
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HOWARD SPRECHER
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Physiological Chemistry, Ohio State University, Columbus, Ohio 43210
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S. K. SANKARAPPE
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Physiological Chemistry, Ohio State University, Columbus, Ohio 43210
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PHILIP NEEDLEMAN
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Physiological Chemistry, Ohio State University, Columbus, Ohio 43210
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Abstract

Using 14C-labeled fatty acids (19:4 ω6, 19:4 ω5, 21:4 ω6, and 21:4 ω7), radiochemical evidence of the formation of α-nor-, ω-nor-, α-homo-, and ω-homoprostaglandin endoperoxides (PGH2), prostacyclins (PGI2), and thromboxanes (TA2) was obtained. Investigation of the biological activities of these compounds indicates that, although 21:4 ω6 is a substrate for cyclooxygenase and its endoperoxide, α-homo-PGH2, is a substrate for prostacyclin synthetase and thromboxane synthetase, α-homo-PGH2, α-homo-PGI2, and α-homo-TA2 are inactive on all receptors studied. In contrast, 19:4 ω5, precursor to ω-nor-PGs, and 19:4 ω6, precursor to α-nor-PGs, form endoperoxides which are not only substrates of prostacyclin synthetase and thromboxane synthetase, but also aggregate platelets and contract rabbit aorta spiral strips. Surprisingly, both α-nor-TA2 and ω-nor-TA2 are partial agonists at vascular smooth muscle receptors but, unlike their respective endoperoxides, do not aggregate washed human platelets. In contrast, 21:4 ω7 is converted to ω-homo-PGH2 and ω-homo-TA2, which aggregate platelets and are full agonists of vascular smooth muscle receptors. In addition to the radiochemical studies, the thromboxanes are identified by their lability in aqueous solution and the inhibition of their formation by the thromboxane synthetase inhibitor imidazole. Bovine aorta microsomes synthesize ω-nor-PGI2, which is a partial agonist, and ω-homo-PGI2, which is a full agonist when evaluated for the ability to relax bovine coronary artery spirals. Although we found radiochemical evidence for the synthesis of α-nor-PGI2 and α-homo-PGI2, these compounds appear to be biologically inactive. The prostacyclin synthetase inhibitor 15-hydroperoxy-arachidonic acid blocks the formation of α-nor-PGI2, ω-nor-PGI2, α-homo-PGI2, and ω-homo-PGI2 as measured by either radiochemical or biological assay.

  • Copyright © 1981 by The American Society for Pharmacology and Experimental Therapeutics

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Molecular Pharmacology
Vol. 19, Issue 2
1 Mar 1981
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Research ArticleArticle

Analogues of Arachidonic Acid Used To Evaluate Structural Determinants of Prostaglandin Receptor and Enzyme Specificities

LOUISE E. LEDUC, ANGELA A. WYCHE, HOWARD SPRECHER, S. K. SANKARAPPE and PHILIP NEEDLEMAN
Molecular Pharmacology March 1, 1981, 19 (2) 242-247;

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Research ArticleArticle

Analogues of Arachidonic Acid Used To Evaluate Structural Determinants of Prostaglandin Receptor and Enzyme Specificities

LOUISE E. LEDUC, ANGELA A. WYCHE, HOWARD SPRECHER, S. K. SANKARAPPE and PHILIP NEEDLEMAN
Molecular Pharmacology March 1, 1981, 19 (2) 242-247;
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