title: GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog.
abstract: Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by beta3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective beta3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective beta3-AR agonist, (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid (GW427353; solabegron) on bladder function in the dog using in vitro and in vivo techniques. GW427353 stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human beta3-AR, with an EC50 value of 22 +/- 6 nM and an intrinsic activity 90% of isoproterenol. At concentrations of 10,000 nM, GW427353 produced a minimal response in cells expressing either beta1-ARs or beta2-ARs (maximum response <10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective beta-AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have beta3-AR antagonist activity). The relaxation was unaffected by atenolol, a selective beta1-AR antagonist, or (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118551), a selective beta2-AR antagonist. GW427353 increased the volume required to evoke micturition in the anesthetized dog following acetic acid-evoked bladder irritation, without affecting the ability of the bladder to void. GW427353-evoked effects on bladder parameters in vivo were inhibited by bupranolol. The present study demonstrates that selective activation of beta3-AR with GW427353 evokes bladder relaxation and facilitates bladder storage mechanisms in the dog.
authors.affiliation: Department of Cardiovascular and Urogenital Biology, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Rd., P.O. Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hicks
authors.forename: Gerald P
authors.initials: GP
authors.lastname: McCafferty
authors.forename: Erin
authors.initials: E
authors.lastname: Riedel
authors.forename: Nambi
authors.initials: N
authors.lastname: Aiyar
authors.forename: Mark
authors.initials: M
authors.lastname: Pullen
authors.forename: Christopher
authors.initials: C
authors.lastname: Evans
authors.forename: Trudy D
authors.initials: TD
authors.lastname: Luce
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coatney
authors.forename: Gian C
authors.initials: GC
authors.lastname: Rivera
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Westfall
authors.forename: J Paul
authors.initials: JP
authors.lastname: Hieble
mesh_terms: D019342:Acetic Acid; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006801:Humans; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D012018:Reflex; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014554:Urination / Q000187:drug effects*
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000814:Aniline Compounds; D001565:Benzoates; D001713:Biphenyl Compounds; C523977:solabegron; D000242:Cyclic AMP; D019342:Acetic Acid