Biochemical characterization of a new highly cardioselective β-adrenoceptor antagonist

M. Gobbi, T. Mennini, E. Ratti

Research output: Contribution to journalArticle

Abstract

PO160 (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 cyclase activity coupled to β-adrenoceptors. The data indicate that PO160 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. PO160's selectivity between cardiac β1- and β2-receptors was 1388, about 60 times that for metoprolol. Analysis of the thermodynamic characteristics of PO160'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 PO160 is a potent, specific and selective β1-adrenoceptor antagonist, and give a molecular explanation for the cardioselective activity found in pharmacological tests.

Original languageEnglish
Pages (from-to)243-246
Number of pages4
JournalJournal of Pharmacy and Pharmacology
Volume40
Issue number4
Publication statusPublished - 1988

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Pharmacology

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