This project continues tests of the hypothesis that adenosine is a physiological regulator of coronary blood flow and cardiac performance, focusing on the structure-activity relationships (SAR) of agonists and antagonists at the adenosine receptors of the cardiac atria and of coronary arteries. The research plan calls for the development of new systheses of novel 2-substituted and 2,6-disubstituted N-ethyl adenosine-5'-uronamides, some of which will be suitable for radiolabelling, photoaffinity radiolabelling and as ligands for affinity chromatography. Biological studies will use the SARs of adenosine analogs to map the cardiac atrial receptors which mediate the negative chronotropic and inotropic effects of adenosine and to compare these receptors with authentic A1 adenosine receptors. Other analgos serve to map the topography of the purine C-2 region and ribose domain of the A2 receptors in cultured cell lines and to see how well these in vitro systems predict coronary vasoactivity in vivo. Studies such as these provide the basis for the rational design of drugs that exploit the antiarrythmic, anticoagulant and vasodilatory properties of adenosine.
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