Selectivity and Maximum Response of Vibegron and Mirabegron for β-Adrenergic Receptors.

BACKGROUND

The β-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-adrenergic receptors.

METHODS

Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing β-, Chinese hamster ovary cells expressing β-, and human embryonic kidney 293 cells expressing β-adrenergic receptors. Cells were incubated with vibegron, mirabegron, or control (β and β, isoproterenol; β, 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-adrenergic receptors with vibegron or mirabegron resulted in concentration-dependent β-adrenergic receptor responses. Mean (SEM) half-maximal effective concentration values at β-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-adrenergic activity relative to isoproterenol was 104% for vibegron and 88% for mirabegron. Maximum response at β-adrenergic receptors was 99.2% for vibegron and 80.4% for mirabegron. β-adrenergic activity was 0% and 3% for vibegron and mirabegron, respectively; β-adrenergic activity was 2% and 15%, respectively.

CONCLUSIONS

Vibegron showed no measurable β and low β activity compared with mirabegron, which showed low β and some β activity. Both showed considerable selectivity at β-adrenergic receptors; however, vibegron demonstrated near-exclusive β activity and a higher maximum β response.