Characterization of an sup 125 I-labeled thromboxane A2/prostaglandin H2 receptor agonist

Stable synthetic mimetics of thromboxane (TX) A2 and prostaglandin (PG) H2 have been synthesized and reported to stimulate platelets and vascular smooth muscle. The synthetic agonists induce aggregation of isolated platelets and contraction of vascular tissue. The tritiated agonists (3H)U46619 and (...

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Published inThe Journal of pharmacology and experimental therapeutics Vol. 251:2
Main Authors Morinelli, T.A., Oatis, J.E. Jr, Okwu, A.K., Mais, D.E., Mayeux, P.R., Masuda, A., Knapp, D.R., Halushka, P.V.
Format Journal Article
LanguageEnglish
Published United States 01.11.1989
Subjects
550201 - Biochemistry- Tracer Techniques
AFFINITY
ANIMALS
BASIC BIOLOGICAL SCIENCES
BETA DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD PLATELETS
BLOOD VESSELS
BODY
BODY FLUIDS
CARDIOVASCULAR SYSTEM
CHEMICAL COMPOSITION
DAYS LIVING RADIOISOTOPES
ELECTRON CAPTURE RADIOISOTOPES
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ISOTOPES
KINETICS
MAMMALS
MAN
MATERIALS
MEMBRANE PROTEINS
MUSCLES
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANS
PRIMATES
PROSTAGLANDINS
PROTEINS
RADIOASSAY
RADIOISOTOPES
REACTION KINETICS
RECEPTORS
VERTEBRATES
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Summary:Stable synthetic mimetics of thromboxane (TX) A2 and prostaglandin (PG) H2 have been synthesized and reported to stimulate platelets and vascular smooth muscle. The synthetic agonists induce aggregation of isolated platelets and contraction of vascular tissue. The tritiated agonists (3H)U46619 and (3H)U44069 have been used in radioligand binding studies to characterize platelet and vascular smooth muscle TXA2/PGH2 receptors, but have limited usefulness due to their low specific activities and variable specific binding. In an attempt to overcome these problems, we have synthesized a stable, high affinity, 125I-radiolabeled TXA2/PGH2 receptor agonist, (1S-(1 alpha, 2 beta (5Z), 3 alpha(1E,3S*), 4 alpha))-7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo - (2.2.1)heptan-2-yl)-5-heptenoic acid (I-BOP). I-BOP induced shape change, increased intracellular free calcium concentrations and aggregated isolated human platelets (EC50 = 0.21 +/- 0.05 nM, n = 3; 4.1 +/- 1.1 nM, n = 4; 10.8 +/- 3 nM, n = 9, respectively). The kinetically determined Kd was 1.02 +/- 0.33 nM (kobs = 0.19 +/- 0.05 min-1, k-1 = 0.097 +/- 0.02 min-1, k1 = 0.119 +/- 0.03 min-1 M, n = 4). Equilibrium binding studies of (125I)BOP to isolated human platelets indicated one class of high affinity sites, Kd = 2.2 +/- 0.3 nM and a maximum binding of 0.028 +/- 0.002 x 10(-12) mol/10(7) platelets (1699 +/- 162 sites/platelet, n = 9).
ISSN:0022-3565
1521-0103