Selectivity and Maximum Response of Vibegron and Mirabegron for β(3)-Adrenergic Receptors

BACKGROUND: The β(3)-adrenergic agonists vibegron and mirabegron have shown favorable safety profiles and efficacy for the treatment of overactive bladder. However, β-adrenergic receptors are also found outside the bladder, which could lead to off-target activity. OBJECTIVE: This study assessed the selectivity of vibegron and mirabegron for β-adrenergic receptors and the maximal effect and potency for β(3)-adrenergic receptors. METHODS: Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing β(1)-, Chinese hamster ovary cells expressing β(2)-, and human embryonic kidney 293 cells expressing β(3)-adrenergic receptors. Cells were incubated with vibegron, mirabegron, or control (β(1) and β(3), isoproterenol; β(2), procaterol). Responses were quantified using homogeneous time-resolved fluorescence of cyclic adenosine monophosphate and were normalized to the respective control. Half-maximal effective concentration and maximum response values were determined by nonlinear least-squares regression analysis. RESULTS: Activation of β(3)-adrenergic receptors with vibegron or mirabegron resulted in concentration-dependent β(3)-adrenergic receptor responses. Mean (SEM) half-maximal effective concentration values at β(3)-adrenergic receptors were 2.13 (0.25) nM for vibegron and 10.0 (0.56) nM for mirabegron. At a concentration of 10 µM, β(3)-adrenergic activity relative to isoproterenol was 104% for vibegron and 88% for mirabegron. Maximum response at β(3)-adrenergic receptors was 99.2% for vibegron and 80.4% for mirabegron. β(1)-adrenergic activity was 0% and 3% for vibegron and mirabegron, respectively; β(2)-adrenergic activity was 2% and 15%, respectively. CONCLUSIONS: Vibegron showed no measurable β(1) and low β(2) activity compared with mirabegron, which showed low β(1) and some β(2) activity. Both showed considerable selectivity at β(3)-adrenergic receptors; however, vibegron demonstrated near-exclusive β(3) activity and a higher maximum β(3) response.