Brucker Benjamin M, King Jennifer, Mudd Paul N, McHale Kimberly
Departments of Urology and Obstetrics and Gynecology, NYU Langone Health, New York, New York.
Urovant Sciences, Irvine, California.
Curr Ther Res Clin Exp. 2022 May 14;96:100674. doi: 10.1016/j.curtheres.2022.100674. eCollection 2022.
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.
This study assessed the selectivity of vibegron and mirabegron for β-adrenergic receptors and the maximal effect and potency for β-adrenergic receptors.
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.
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.
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.
β-肾上腺素能激动剂维贝格隆和米拉贝隆已显示出良好的安全性和治疗膀胱过度活动症的疗效。然而，β-肾上腺素能受体也存在于膀胱之外，这可能导致脱靶活性。
本研究评估了维贝格隆和米拉贝隆对β-肾上腺素能受体的选择性以及对β-肾上腺素能受体的最大效应和效价。
使用表达β-的中国仓鼠卵巢-K1细胞、表达β-的中国仓鼠卵巢细胞和表达β-肾上腺素能受体的人胚肾293细胞进行功能性细胞试验。细胞与维贝格隆、米拉贝隆或对照（β和β，异丙肾上腺素；β，丙卡特罗）孵育。使用环磷酸腺苷的均相时间分辨荧光对反应进行定量，并将其标准化为各自的对照。通过非线性最小二乘回归分析确定半数最大有效浓度和最大反应值。
用维贝格隆或米拉贝隆激活β-肾上腺素能受体会导致浓度依赖性的β-肾上腺素能受体反应。维贝格隆在β-肾上腺素能受体处的平均（标准误）半数最大有效浓度值为2.13（0.25）nM，米拉贝隆为10.0（0.56）nM。在10 μM的浓度下，维贝格隆相对于异丙肾上腺素的β-肾上腺素能活性为104%，米拉贝隆为88%。维贝格隆在β-肾上腺素能受体处的最大反应为99.2%，米拉贝隆为80.4%。维贝格隆和米拉贝隆对β-肾上腺素能的活性分别为0%和3%；对β-肾上腺素能的活性分别为2%和15%。
与米拉贝隆相比，维贝格隆未显示出可测量的β活性且β活性较低，米拉贝隆显示出较低的β活性和一些β活性。两者在β-肾上腺素能受体处均表现出相当的选择性；然而，维贝格隆表现出近乎专一的β活性和更高的最大β反应。
