LK 204–545, a highly selective β1-adrenoceptor antagonist at human β-adrenoceptors

Abstract LK 204–545 ((±)-1-(2-(3-(2-cyano-4-(2-cyclopropyl-methoxy-ethoxy)phenoxy)-2-hydroxy-propyl-amino)-ethyl)-3-(4-hydroxyphenyl) urea), an antagonist that possesses high β 1 -/β 2 -selectivity in the rat, and a range of cardio-selective and non-selective β-adrenoceptor antagonists were examined to compare their radioligand binding affinities for human β 1 -, β 2 - and β 3 -adrenoceptors transfected into CHO cells. LK 204–545 and CGP 20712A displayed the highest β 1 -/β 2 - (∼1800 and ∼650, respectively) and β 1 -/β 3 -selectivity (∼17 000 and ∼2200, respectively) at human β-adrenoceptors with LK 204–545 being ∼2.75-fold more β 1 -/β 2 -selective and ∼8-fold β 1 -/β 3 -selective than CGP 20712A. The high potency of LK 204–545 at transfected human β 1 -adrenoceptors and in functional models of rat β 1 -adrenoceptors together with its high selectivity, identify it as a useful ligand for studying β 1 -adrenoceptors and suggest that it may be the preferred ligand for human β-adrenoceptor studies.