GW427353 (Solabegron), a Novel, Selective β₃-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 ␤ 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)

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

“…The response against KClinduced tone was not affected by the β 1 -adrenoceptor antagonist CGP 20,712A or the β 2 -adrenoceptor antagonist ICI 118,551,but surprisingly also not by the general β-adrenoceptor antagonist SR 59,230A (Niclauß et al 2006). In contrast to the other agonists, bladder relaxation by solabegron has not been reported in rats as the primary animal species but has been in dogs (Hicks et al 2007). In this species, solabegron caused concentration-dependent relaxation against KCl-induced tone, but a smaller but substantial relaxation was also seen in time control experiments with vehicle addition.…”

“…In propofol-anesthetized female dogs, bladder irritation was induced by intravesical acetic acid instillation; in this model, i.v. administration of solabegron increased micturition volume threshold but did not significantly affect voided volume, voiding efficiency, bladder contraction amplitude, and duration (Hicks et al 2007). Within that study, the solabegron dose increasing micturition volume threshold decreased mean arterial pressure by 35 mm Hg and increased heart rate by 97 bpm.…”

“…In the first series, the EC 50 of solabegron at human β 1 -, β 2 -, and β 3 -adrenoceptors was 1,259, 3,981, and 3.98 nM, respectively, as compared to 1.0, 0.16, and 3.16 nM, respectively, for isoprenaline, i.e., solabegron was 1,000-and 316-fold selective for β 3 -vs. β 1 -or β 2 -adrenoceptors (Uehling et al 2006); in these experiments, the efficacy of solabegron relative to isoprenaline was 0.79 at β 3 -adrenoceptors but 0.02 and 0.05 at β 1 -or β 2 -adrenoceptors, respectively. In a second series of experiments, solabegron stimulated cyclic AMP accumulation via human β 3 -adrenoceptors with an EC 50 of 6.9 nM as compared to 3.3 nM for isoprenaline, and the efficacy of solabegron relative to isoprenaline was 0.89 (Hicks et al 2007). In these experiments in concentrations up to 10 μM, solabegron caused cyclic AMP accumulation of only 4.2 and 8.8 % of isoprenaline values at β 1 -and β 2 -adrenoceptors, respectively.…”

“…In single-concentration experiments, relaxation by solabegron was not affected by the β 1 -selective atenolol or the β 2 -selective ICI 118,551 but attenuated by the non-selective antagonist bupranolol. The non-selective antagonist SR 59,230A (Niclauß et al 2006) attenuated the response to solabegron but also caused some relaxation in the absence of solabegron (Hicks et al 2007). Relaxation responses to SR 59,230A in the absence of exogenous agonist had also been reported in rat and human bladder (Frazier et al 2011).…”

The physiological function of lower urinary tract smooth muscle

“…There is currently active interest in developing β-receptor agonists suitable for clinical use as a treatment for bladder overactivity (Malmgrem et al, 1987;Hicks et al, 2007;Leon et al, 2008).…”