PT - JOURNAL ARTICLE AU - Alexandra Hicks AU - Gerald P. McCafferty AU - Erin Riedel AU - Nambi Aiyar AU - Mark Pullen AU - Christopher Evans AU - Trudy D. Luce AU - Robert W. Coatney AU - Gian C. Rivera AU - Timothy D. Westfall AU - J. Paul Hieble TI - GW427353 (Solabegron), a Novel, Selective β<sub>3</sub>-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog AID - 10.1124/jpet.107.125757 DP - 2007 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 202--209 VI - 323 IP - 1 4099 - http://jpet.aspetjournals.org/content/323/1/202.short 4100 - http://jpet.aspetjournals.org/content/323/1/202.full SO - J Pharmacol Exp Ther2007 Oct 01; 323 AB - Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by β3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective β3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective β3-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 β3-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 β1-ARs or β2-ARs (maximum response &lt;10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective β-AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have β3-AR antagonist activity). The relaxation was unaffected by atenolol, a selective β1-AR antagonist, or (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118551), a selective β2-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 β3-AR with GW427353 evokes bladder relaxation and facilitates bladder storage mechanisms in the dog. The American Society for Pharmacology and Experimental Therapeutics