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

• Published in: Journal of Pharmacological Sciences 2003, Vol.92(4), pp.411-419
• Main Authors: Tomiyama, Yoshitaka, Murakami, Makoto, Hayakawa, Kohichi, Akiyama, Katsuyoshi, Yamazaki, Yoshinobu, Kojima, Masami, Shibata, Nobuo, Akahane, Masuo
• Format: Article
• Language: English
• Subjects: Acetates - chemistry; Acetates - pharmacology; Adrenergic beta-Agonists - chemistry; Adrenergic beta-Agonists - pharmacology; Animals; Dogs; Dose-Response Relationship, Drug; Female; In Vitro Techniques; KUL-7211; Male; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Pregnancy; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta - physiology; relaxation; ureter; Ureter - drug effects; Ureter - physiology; β2-adrenoceptor; β3-adrenoceptor
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.92.411

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, 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.