Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist

J Pharmacol Exp Ther. 1985 Aug;234(2):435-41.

Abstract

SQ 29,548, [1S-[1 alpha,2 beta (5Z),3 beta,4 alpha]-7-[3-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid, and the racemic modification, +/- SQ 29,548, were identified as active inhibitors of human platelet aggregation induced by arachidonic acid, collagen, epinephrine (2 degrees phase) and the thromboxane A2 mimics, 9,11-azo prostaglandin (PG) H2 and 11,9-epoxymethano PGH2. SQ 29,548 did not inhibit aggregation induced by ADP, and it did not prevent PGD2 from inhibiting ADP-induced platelet aggregation. Inhibition of platelet function by +/- SQ 29,548 was not associated with inhibition of cyclooxygenase or thromboxane synthetase or with changes in platelet cyclic AMP. In guinea-pig trachea and rat aorta, +/- SQ 29,548 competitively antagonized the activity of 9,11-azo PGH2 with pA2 values of 7.8 and 8.4, respectively. The chiral compound, SQ 29,548 competitively antagonized contractions of guinea-pig tracheal spirals caused by 11,9-epoxymethano PGH2 with a pA2 value of 9.1. The +/- SQ 29,548 competitively antagonized tracheal responses to 11,9-epoxymethano PGH2 and PGD2 with pA2 values of 8.2 and 8.3, respectively, indicating that PGD2 and the thromboxane A2 mimic probably act at the same receptor in guinea-pig tracheal smooth muscle. Contractions of guinea-pig tracheal spirals induced by PGE2 were not antagonized, and those caused by PGF2 alpha were only partially antagonized by +/- SQ 29,548. The +/- SQ 29,548 also significantly inhibited the aorta contracting activity of 11,9-epoxymethano PGH2 (pA2 = 9.1) and thromboxane A2 released from perfused guinea-pig lungs upon arachidonic acid challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

MeSH terms

  • Adenylyl Cyclases / analysis
  • Animals
  • Arachidonic Acid
  • Arachidonic Acids / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic
  • Dose-Response Relationship, Drug
  • Fatty Acids, Unsaturated
  • Guinea Pigs
  • Humans
  • Hydrazines / pharmacology*
  • In Vitro Techniques
  • Male
  • Muscle Contraction / drug effects
  • Platelet Aggregation / drug effects
  • Rats
  • Stereoisomerism
  • Stomach / drug effects
  • Thromboxane A2 / antagonists & inhibitors*
  • Thromboxanes / antagonists & inhibitors*
  • Trachea / drug effects

Substances

  • Arachidonic Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • Fatty Acids, Unsaturated
  • Hydrazines
  • Thromboxanes
  • Arachidonic Acid
  • Thromboxane A2
  • SQ 29548
  • Adenylyl Cyclases