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

Igawa, Yasuhiko; Michel, Martin C.

doi:10.1007/s00210-012-0824-1

Cited by 77 publications

(61 citation statements)

References 38 publications

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“…More hope comes from b 3 -adrenoceptor agonists which have entered clinical development such as mirabegron, ritobegron, and solabegron; for experimental use of these compounds, it should be considered that mirabegron and ritobegron may preferentially act on the human and rat ortholog, respectively (Igawa et al, 2012;Igawa and Michel, 2013).…”

Section: Unique Ligand Recognition Profilementioning

confidence: 99%

The Odd Sibling: Features ofβ₃-Adrenoceptor Pharmacology

2014

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b 3 -Adrenoceptor agonists have recently been introduced for the treatment of overactive urinary bladder syndrome. Their target, the b 3 -adrenoceptor, was discovered much later than b 1 -and b 2 -adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the b 3 -adrenoceptor a less-understood subtype. This article discusses three aspects of b 3 -adrenoceptor pharmacology. First, the ligand-recognition profile of b 3 -adrenoceptors differs considerably from that of the other two subtypes, i.e., many antagonists considered as nonselective actually are b 3 -sparing, including propranolol or nadolol. Many agonists and antagonists classically considered as being b 3 -selective actually are not, including BRL 37,344 ( (6) . Moreover, the binding pocket apparently differs between the human and rodent b 3 -adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of b 3 -adrenoceptors is more restricted than that of other subtypes, particularly in humans; this makes extrapolation of rodent findings to the human situation difficult, but it may result in a smaller potential for side effects. The role of b 3 -adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, b 3 -adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit downregulation and/or desensitization in some, but not other, cell types and tissues. When desensitization occurs, it most often is at the level of mRNA or signaling molecule expression. All three of these factors have implications for future studies to better understand the b 3 -adrenoceptor as a novel pharmacological target.

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Section: Unique Ligand Recognition Profilementioning

confidence: 99%

The Odd Sibling: Features ofβ₃-Adrenoceptor Pharmacology

2014

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“…It is generally considered, based on animal studies, that the activity in the adrenergic nerves keeps the bladder relaxed and the urethra contracted during filling [4,9]. However, the importance of the sympathetic input for human bladder function during the storage phase has not been established.…”

Section: Adrenergic Nerves In the Bladder And Urethramentioning

confidence: 99%

“…β-AR agonists, including mirabegron, have been suggested to relieve OAB symptoms through various mechanisms, e.g., direct relaxation of detrusor muscle by stimulation of cyclic AMP (cAMP) generation [4,5], opening of potassium channels [6,7], inhibition of spontaneous contractile activity in the bladder [8,9], and reduction in bladder afferent activity [9,10]. However, the site(s) and mechanism(s) of action of β 3 -AR agonists have not been established and has been the subject of several recent studies.…”

Section: Introductionmentioning

confidence: 99%

On the Site and Mechanism of Action of β3-Adrenoceptor Agonists in the Bladder

Andersson

2017

Int Neurourol J

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The clinical success of mirabegron as the first β3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β3-AR stimulation have still not been established. The recent demonstration of β3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β3-ARs can be found these structures. However, recent studies suggest that the β3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.

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“…Drugs such as mirabegron have been reported to decrease voiding frequency, reduce incontinence episodes and consequently, improve quality of life (Chapple et al, 2014;Sacco et al, 2014). Although these drugs were designed to relax the detrusor via a direct action on detrusor cell β 3 -adrenoceptors and so alleviate the symptoms of overactivity (Igawa and Michel, 2013), evidence is now emerging that additional modes of actions should be considered. The plasma concentrations of therapeutic doses of mirabegron are in the order of 30-75 nM (Krauwinkel et al, 2012).…”

Section: Introductionmentioning

confidence: 99%