Pharmacological Profile of KUL-7211, a Selective β-Adrenoceptor Agonist, in Isolated Ureteral Smooth Muscle

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Since, in the human ureter, both β₂- and β₃-adrenoceptors mediate adrenergic-stimulation-induced relaxation, selective β₂-/β₃-adrenoceptor agonists might prove clinically useful for relieving ureteral colic and promoting stone passage. We evaluated the β-adrenoceptor subtype selectivity and ureteral-relaxing efficacy of (−)-2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenyloxy]acetic acid (KUL-7211), a new β-adrenoceptor agonist, in vitro. In rat isolated organs, its selectivities, for inhibition of spontaneous uterine contraction (mediated via β₂-adrenergic stimulation) and inhibition of colonic contraction (via β₃-adrenergic stimulation) versus increase in atrial rate (via β₁-adrenergic stimulation), were 56.3 and 242.2, respectively. KUL-7211 relaxed 80-mM-KCl-induced tonic contractions in both rabbit (pD₂ value: 5.86 ± 0.13, whose ureteral relaxation is mediated via β₂-adrenergic stimulation) and canine (pD₂ value: 6.52 ± 0.16, via β₃-adrenergic stimulation) isolated ureters in a concentration-dependent manner. These KUL-7211-induced relaxing effects were antagonized by ICI-118,551 (selective β₂-adrenoceptor antagonist, pK_B value: 8.91 ± 0.24) in the rabbit ureter and by bupranolol (non-selective β-adernoceptor antagonist, pK_B value: 6.85 ± 0.12) in the canine ureter. KUL-7211 also reduced the spontaneous rhythmic contraction in a canine ureteral spiral preparation in a concentration-dependent manner, the pD₂ value being 6.83 ± 0.20. These data clearly demonstrate that KUL-7211 selectively stimulates both ureteral β₂- and β₃-adrenoceptors and potently relaxes ureteral smooth muscle. KUL-7211 may be a novel and useful medication for relieving ureteral colic and promoting stone passage in urolithiasis patients.