Biochemical Characterization of a New Highly Cardioselective β-Adrenoceptor Antagonist

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Abstract
— P0160 (1‐phenyl‐3‐(2‐(3‐(2‐cyanophenoxy)‐2‐hydroxypropyl)amino) ethylhydantoin HCl) is an aryloxypropanolamine which contains a ureido group as part of the hydantoin ring. This molecule was synthesized to obtain a more cardioselective β‐adrenoceptor blocker. Preliminary data have shown that it is as potent as propranolol and four times more cardioselective than atenolol in pharmacological tests in‐vitro and in the conscious rat. In the present study we evaluated the interaction of P0160 with β‐adrenoceptors by radioreceptor binding studies and by measuring adenylate cylase activity coupled to β‐adrenoceptors. The data indicate that P0160 binds with nanomolar affinity to β‐adrenoceptors labelled with [3H]DHA in the rat heart, but with micromolar affinity in the rat lung. Its binding is stereospecific, the S‐(−)isomer being 200 times more active than the R‐(+) form. P0160′s selectivity between cardiac β1‐ and β2‐receptors was 1388, about 60 times that for metoprolol. Analysis of the thermodynamic characteristics of P0160′s interaction with rat heart β‐adrenoceptors indicated antagonist properties of the same order of magnitude as propranolol, as confirmed by adenylate cyclase studies. These data indicate that P0160 is a potent, specific and selective β1‐adrenoceptor antagonist, and give a molecular explanation for the cardioselective activity found in pharmacological tests.