8‐pCPT‐Conjugated Cyclic AMP Analogs exert Thromboxane Receptor Antagonistic Properties

Membrane‐permeable 8‐pCPT‐2′‐O‐Me‐cAMP has been shown to specifically activate cAMP‐regulated Epac proteins, without direct effects on protein kinase A and protein kinase G. During isometric tension measurements in thoracic aortic rings from Wistar rats, we observed that 8‐pCPT‐2′‐O‐Me‐cAMP selectively induced a rightward shift of the concentration response curve for the thromboxane mimetic U46619, without altering the contractile response to noradrenaline. We hypothesized that 8‐pCPT‐2′‐O‐Me‐cAMP and similar compounds may function as direct thromboxane receptor antagonists. Indeed, in addition to 8‐pCPT‐2′‐O‐Me‐cAMP, also 8‐pCPT‐cAMP, Rp‐8‐CPT‐cAMPS and 8‐CPT‐adenosine, but not 8‐Bromo‐2′‐O‐Me‐cAMP, induced rightward shifts of the contractile response to U46619. Likewise, 8‐pCPT‐2′‐O‐Me‐cAMP and Rp‐8‐CPT‐cAMPS, but not 8‐Bromo‐2′‐O‐Me‐cAMP, specifically reduced U46619‐induced aggregation of human platelets. In addition, 8‐pCPT‐2′‐O‐Me‐cAMP and Rp‐8‐CPT‐cAMPS completely reversed U46619‐induced reduction of intercellular adhesion molecule‐1 expression and migration of human coronary artery endothelial cells. Most important, the cAMP analogs that reduced the contractile response to U46619 also concentration‐dependently inhibited binding of the thromboxane receptor radioligand [5,6‐3H]SQ29548 to human platelets. We conclude that 8‐pCPT‐conjugated cAMP analogs exert competitive thromboxane receptor antagonistic properties. Supported by the Deutsche Forschungsgemeinschaft and a Rosalind Franklin Fellowship from the University of Groningen.