title: Pharmacological effect of TRK-380, a novel selective human β3-adrenoceptor agonist, on mammalian detrusor strips.
abstract: OBJECTIVE
  To clarify the potential of TRK-380 as a drug for overactive bladder in humans by evaluating the agonistic activities for human β-adrenergic receptors (β-ARs) and the relaxing effects on isolated detrusor strips.
  
  
  METHODS
  The agonistic activities for human β-ARs were evaluated in SK-N-MC cells (for human β(3)-ARs) and Chinese hamster ovary cells expressing human β(1)- or human β(2)-ARs using the cyclic adenosine monophosphate accumulation assay. The relaxing effects on the resting tension in isolated detrusor strips from humans, monkeys, dogs, and rats and on carbachol- or KCl-induced contractions in human detrusor strips were evaluated.
  
  
  RESULTS
  In the cyclic adenosine monophosphate accumulation assay, the agonistic activity of TRK-380 for human β(3)-ARs was potent and equivalent to that of the potent nonselective β-AR agonist isoproterenol and superior to that of selective β(3)-AR agonists, such as BRL-37344 and CL316,243. TRK-380 showed no agonistic activity for human β(1)-ARs and a weak agonistic effect on human β(2)-ARs. In isolated detrusor strips, the concentration-dependent relaxing effects of TRK-380 on the resting tension were equivalent to those of isoproterenol in humans, monkeys, and dogs but weaker than the effects in rats. The selective β(3)-AR antagonist SR59230A shifted the concentration-response curve in a concentration-dependent manner to TRK-380 for the resting tension of human detrusor strips to the right. TRK-380 had a concentration-dependent relaxing effect on the contractile responses to carbachol and KCl in human detrusor strips.
  
  
  CONCLUSIONS
  TRK-380 was a potent and selective human β(3)-AR agonist, and the isolated human detrusor relaxation was mainly mediated by activation of the β(3)-AR. Consequently, TRK-380 might be a promising compound for the treatment of overactive bladder.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Japan. Sayoko_Kanie@nts.toray.co.jp
authors.forename: Sayoko
authors.initials: S
authors.lastname: Kanie
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.forename: Satoru
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Morimoto
authors.forename: Nana
authors.initials: N
authors.lastname: Hareyama
authors.forename: Seiji
authors.initials: S
authors.lastname: Okazaki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kobayashi
authors.forename: Ko
authors.initials: K
authors.lastname: Hasebe
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakao
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hayashi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Rikiya
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ozono
mesh_terms: D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016015:Logistic Models; D009119:Muscle Contraction / Q000187:drug effects; D009924:Organ Culture Techniques; D011412:Propanolamines / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D000242:Cyclic AMP