GW427353 (Solabegron), a Novel, Selective β3-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog

@article{Hicks2007GW427353A,
  title={GW427353 (Solabegron), a Novel, Selective $\beta$3-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog},
  author={Alexandra Hicks and Gerald P. McCafferty and Erin S. Riedel and Nambi V. Aiyar and Mark A. Pullen and Christopher Evans and Trudy D Luce and Robert W. Coatney and Gian C Rivera and Timothy D. Westfall and Jacob Paul Hieble},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2007},
  volume={323},
  pages={202 - 209}
}
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… 

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References

SHOWING 1-10 OF 39 REFERENCES

Characterization of β-adrenoceptor subtypes in the ferret urinary bladder in vitro and in vivo

Agonistic activity of SR59230A at atypical beta-adrenoceptors in guinea pig gastric fundus and duodenum.

The positive chronotropic effect induced by BRL 37344 and CGP 12177, two beta-3 adrenergic agonists, does not involve cardiac beta adrenoceptors but baroreflex mechanisms.

The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure and the presence of a beta-3 adrenoceptor and its involvement in the control of heart rate was investigated in the dog.

Characterization of beta-adrenoceptor subtypes in the ferret urinary bladder in vitro and in vivo.

The present functional study provides the first evidence that relaxation of the ferret detrusor by beta-adrenoceptor activation is mediated mainly via the beta(3)-adrenOceptor, as in the humandetrusor.

Characterization of beta-adrenoceptor subtype in bladder smooth muscle in cynomolgus monkey.

The present functional study provides the first evidence that relaxation of the monkey detrusor by beta-adrenoceptor activation is mediated via the beta3-subtype.

Functional identification of rat atypical β‐adrenoceptors by the first β3‐selective antagonists, aryloxypropanolaminotetralins

APATs are support APATs as the first potent, orally effective selective antagonists at β3‐adrenoceptors, and provide final unambiguous evidence that β3 • adrenoceptor‐blocking agents underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats.

Functional identification of rat atypical beta-adrenoceptors by the first beta 3-selective antagonists, aryloxypropanolaminotetralins.

Findings support APATs as the first potent, orally effective selective antagonists at beta 3-adrenoceptors, and provide final unambiguous evidence that beta 1 and 2 beta- adrenoceptor-blocking agents underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats.

Functional Characterization of β-adrenoceptor Subtypes in the Canine and Rat Lower Urinary Tract

In the dog the relaxing effects of isoprenaline in the distal urethra were about half those seen in the detrusor and trigone, and the maximal relaxation to each agonist wa...

Effect of (R)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective β3-Adrenoceptor Agonist, on Bladder Function

The suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence is suggested.

Evidence for Pleiotropic Signaling at the Mouse β3-Adrenoceptor Revealed by SR59230A [3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol Oxalate]

This study examines the action of the β3-adrenoceptor antagonist SR59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] at cloned mouse β3-adrenoceptors