Biochemical Characterization of a New Highly Cardioselective β‐Adrenoceptor Antagonist

— 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.