Four new beta-adrenoceptor blocking agents carrying tyramine as the amino moiety were synthesized and the distribution of their I-125-tagged derivatives evaluated in rats. This distribution was compared with the distribution of various agonists and antagonists labeled with H-3 and C-14, and with the in vitro binding affinity of the new derivatives. A radioiodinated derivative of a cardioselective blocker, alprenolol, showed poor blood clearance and no cardiac selectivity. A derivative of another cardioselective blocker, practolol, showed a promising heart-to-blood ratio (ca. 19) and cardioselectivity with a heart-to-lung ratio of ca. 2. Two additional practolol analogs showed no improvement over the practolol derivative; because of the increased lipophilicity of these derivatives, blood clearance and cardioselectivity were diminished. An inverse correlation is suggested between the dissociation constant for the beta adrenoceptor in the lung and the heart-to-blood and heart-to-lung values. We conclude that polarity plays an important role in the blood clearance and cardioselectivity of these beta-adrenoceptor derivatives.
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