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

• Published in: Journal of Pharmacological Sciences 2003-08, Vol.92 (4), p.411-419
• Main Authors: Yoshitaka Tomiyama, Makoto Murakami, Kohichi Hayakawa, Katsuyoshi Akiyama, Yoshinobu Yamazaki, Masami Kojima, Nobuo Shibata, Masuo Akahane
• Format: Article
• Language: Japanese
• ISSN: 1347-8613

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-KC1-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, pKB Value： 8.91±0.24) in the rabbit ureter and by bupranolol (non-selective β-adernoceptor antagonist, pKB 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.