Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322

Abstract

This study aimed to characterize the β-adrenoceptor (β-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel β3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the β-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known β3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC(50) of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent pK (B) 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

“…The only human tissue in which a large body of data exists on β 3 -adrenoceptors is the target tissue for the clinically used compounds, i.e. the urinary bladder, and even in the bladder, most of the expression information is inferred from functional studies (Michel and Vrydag 2006;Igawa et al 2012).…”

The Odd Sibling: Features ofβ3-Adrenoceptor Pharmacology

“…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).…”

“…Human bladder relaxation is mediated predominantly if not exclusively by the b 3 -adrenoceptor subtype (Igawa et al, 2012), and b-adrenoceptor agonists are effective in every experimental model of bladder dysfunction ever investigated (Michel and Barendrecht, 2008). Accordingly, two b 3 -adrenoceptor agonists have shown efficacy in placebocontrolled studies, i.e., solabegron (Ohlstein et al, 2012) and mirabegron (Chapple et al, 2014), the latter recently having obtained regulatory approval.…”

Investigation of Drug–Drug Interactions Between Ritobegron, a Selective β3‐Adrenoceptor Agonist, With Probenecid in Healthy Men

“…To measure the KUC-7322 concentrations, blood samples (2 mL per time) were collected in vacuum blood collection tubes containing ethylenediaminetetraacetic acid disodium salt, sodium fluoride, and heparin at the following times after administration of ritobegron: 0.25, 0.5, 1, 1.5, 2, 3, 4,6,8,12,14,24,36, and 48 hours. Blood samples were centrifuged (3000 rpm) at 4˚C for 10 minutes and separated.…”