Investigation of beta(2)-adrenoceptor subtype selectivity and organ specificity for bedoradrine (KUR-1246), a novel tocolytic beta-adrenergic receptor stimulant.

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate the beta-adrenergic receptor (beta-AR) selectivity, organ specificity and efficacy of delaying the onset of spontaneous delivery of bedoradrine (KUR-1246), a novel uterine relaxant. METHODS: beta-AR selectivity was evaluated in terms of the amount of cyclic adenosine monophosphate produced by bedoradrine, ritodrine and isoprenaline in Chinese hamster ovary cells expressing human beta(1)-, beta(2)-AR or beta(3)-AR. Inhibition of contractions of the atrium, trachea and proximal colon by bedoradrine were compared with those of the uterus in pregnant rats using an organ bath method. Finally, the delaying effect of bedoradrine on spontaneous labor was evaluated by an in vivo study using term pregnant rats. RESULTS: EC(50) values of bedoradrine for cyclic adenosine monophosphate production in Chinese hamster ovary cells via beta(1)-, beta(2)- and beta(3)-AR were 2400 +/- 30, 2.9 +/- 0.10 and 363 +/- 3 nmol/L, respectively, indicating that bedoradrine had 832- and 126-fold higher selectivity for beta(2)-AR than for beta(1)- and beta(3)-AR. EC(50) values of bedoradrine for the uterus, atrium, trachea and proximal colon were 1.01 +/- 0.27, 2300 +/- 356, 1610 +/- 299 and 219 +/- 23.5 nmol/L, respectively. Thus, bedoradrine was 2280-, 1590- and 217-fold more specific for the uterus than for the atrium, trachea and proximal colon, respectively. Bedoradrine delayed the spontaneous delivery of 21-day-pregnant rats in a dose-dependent manner. CONCLUSIONS: Bedoradrine is a promising drug for the treatment of preterm labor in obstetrical practice because it has better selectivity for beta(2)-AR and specificity for the uterus than currently used agents and may effectively delay spontaneous delivery.