Vol. 297, Issue 2, 666-671, May 2001

Pharmacological Characterization of KUR-1246, a Selective Uterine Relaxant

Mamoru Kobayashi , Keiko Takeda, Satoshi Murata, Masami Kojima, Masuo Akahane, Yoshihito Inoue, Kenji Kitamura and Tatsuhiko Kawarabayashi

Pharmacology Research, R&D, Kissei Pharmaceutical Co., Ltd., Nagano, Japan (M.K., K.T., S.M., M.K., M.A.); Department of Pharmacology, Fukuoka Dental College, Fukuoka, Japan (K.K.); and Department of Obstetrics and Gynecology, Fukuoka University School of Medicine, Fukuoka, Japan (Y.I., T.K.)

The aim of the present study was to evaluate the efficacy and 2-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 1-, 2-, and 3-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 2-AR antagonist) competitively antagonized the KUR-1246-induced inhibition of spontaneous uterine contractions, but CGP-20712A (selective 1-AR antagonist) and SR-58894A (selective 3-AR antagonist) did not. All -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 1-, 2-, and 3-ARs, the pK_i values being 5.75 ± 0.03, 7.59 ± 0.08, and 4.75 ± 0.03 for 1-, 2-, and 3-ARs, respectively. For the selectivity of KUR-1246 for human 2-AR, we obtained values of 39.2 ([IC₅₀ for 1-AR]/[IC₅₀ for 2-AR]) and 198.2 ([IC₅₀ for 3-AR]/[IC₅₀ for 2-AR]), indicating an apparently higher affinity for human 2-AR than for other -AR subtypes. The present study clearly demonstrated that KUR-1246 is a more selective 2-AR agonist than the drugs presently used for relaxing uterine muscle.