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Investigation of β 2 ‐adrenoceptor subtype selectivity and organ specificity for bedoradrine (KUR‐1246), a novel tocolytic beta‐adrenergic receptor stimulant
Author(s) -
Inoue Yoshihito,
Yoshizato Toshiyuki,
Kawarabayashi Tatsuhiko
Publication year - 2009
Publication title -
journal of obstetrics and gynaecology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.597
H-Index - 50
eISSN - 1447-0756
pISSN - 1341-8076
DOI - 10.1111/j.1447-0756.2008.01001.x
Subject(s) - medicine , chinese hamster ovary cell , ritodrine , tocolytic , adrenergic receptor , uterus , endocrinology , adenosine receptor , receptor , adenosine , tocolytic agent , isoprenaline , adrenergic , fetus , pregnancy , gestation , agonist , biology , preterm labor , stimulation , genetics
Objectives: The aim of this study was to evaluate the beta‐adrenergic receptor (β‐AR) selectivity, organ specificity and efficacy of delaying the onset of spontaneous delivery of bedoradrine (KUR‐1246), a novel uterine relaxant. Methods: β‐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 β 1 ‐, β 2 ‐AR or β 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 β 1 ‐, β 2 ‐ and β 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 β 2 ‐AR than for β 1 ‐ and β 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 β 2 ‐AR and specificity for the uterus than currently used agents and may effectively delay spontaneous delivery.