Abstract

The aim of the present study was to evaluate the efficacy and β2-adrenoceptor (AR) selectivity of KUR-1246, a new uterine relaxant. Inhibition of spontaneous or drug-induced uterine contractions by KUR-1246 was evaluated in pregnant rats and rabbits by an organ bath method or by a balloon method. The selectivity of KUR-1246 was assessed simultaneously in organs isolated from late-pregnant rats. The affinity of KUR-1246 for human β1-, β2-, and β3-ARs was determined using two radioligands. KUR-1246 suppressed both spontaneous and drug-induced contractions in isolated uteri, the rank order of potency being isoproterenol > KUR-1246 > terbutaline > ritodrine. ICI-118551 (selective β2-AR antagonist) competitively antagonized the KUR-1246-induced inhibition of spontaneous uterine contractions, but CGP-20712A (selective β1-AR antagonist) and SR-58894A (selective β3-AR antagonist) did not. All β-AR agonists tested produced significant inhibition of spontaneous uterine contractions in vivo: ED₃₀ value for KUR-1246 was 0.13 μg/kg/min, a potency about 6 times and 400 times greater than that of terbutaline and ritodrine, respectively. In contrast, the positive chronotropic effect was minimal in KUR-1246-treated rats. KUR-1246 displaced radioligand binding to β1-, β2-, and β3-ARs, the pK _i values being 5.75 ± 0.03, 7.59 ± 0.08, and 4.75 ± 0.03 for β1-, β2-, and β3-ARs, respectively. For the selectivity of KUR-1246 for human β2-AR, we obtained values of 39.2 ([IC₅₀ for β1-AR]/[IC₅₀ for β2-AR]) and 198.2 ([IC₅₀ for β3-AR]/[IC₅₀ for β2-AR]), indicating an apparently higher affinity for human β2-AR than for other β-AR subtypes. The present study clearly demonstrated that KUR-1246 is a more selective β2-AR agonist than the drugs presently used for relaxing uterine muscle.