Selectivity and Maximum Response of Vibegron and Mirabegron for β3-Adrenergic Receptors

Background

The β₃-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 β₃-adrenergic receptors.

Methods

Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing β₁-, Chinese hamster ovary cells expressing β₂-, and human embryonic kidney 293 cells expressing β₃-adrenergic receptors. Cells were incubated with vibegron, mirabegron, or control (β₁ and β₃, isoproterenol; β₂, 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 β₃-adrenergic receptors with vibegron or mirabegron resulted in concentration-dependent β₃-adrenergic receptor responses. Mean (SEM) half-maximal effective concentration values at β₃-adrenergic receptors were 2.13 (0.25) nM for vibegron and 10.0 (0.56) nM for mirabegron. At a concentration of 10 µM, β₃-adrenergic activity relative to isoproterenol was 104% for vibegron and 88% for mirabegron. Maximum response at β₃-adrenergic receptors was 99.2% for vibegron and 80.4% for mirabegron. β₁-adrenergic activity was 0% and 3% for vibegron and mirabegron, respectively; β₂-adrenergic activity was 2% and 15%, respectively.

Conclusions

Vibegron showed no measurable β₁ and low β₂ activity compared with mirabegron, which showed low β₁ and some β₂ activity. Both showed considerable selectivity at β₃-adrenergic receptors; however, vibegron demonstrated near-exclusive β₃ activity and a higher maximum β₃ response.