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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

GW427353 (Solabegron), a Novel, Selective ₃-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog

Departments of Cardiovascular and Urogenital Biology (A.H., G.P.M., E.R., N.A., M.P., T.D.W., J.P.H.), Drug Metabolism and Pharmacokinetics (C.E., T.D.L.), and Animal Modeling and Imaging and Laboratory Animal Sciences (R.W.C., G.C.R.), Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by ₃-adrenergic receptors (ARs) in human bladder. Thus, the use of selective ₃-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective ₃-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 ₃-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 ₁-ARs or ₂-ARs (maximum response <10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective -AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have ₃-AR antagonist activity). The relaxation was unaffected by atenolol, a selective ₁-AR antagonist, or (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118551), a selective ₂-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 ₃-AR with GW427353 evokes bladder relaxation and facilitates bladder storage mechanisms in the dog.

Address correspondence to: Dr. Timothy D. Westfall, 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. E-mail: timothy.d.westfall{at}gsk.com

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