Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Azumino, Nagano, Japan.
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Tochigi, Japan.
PLoS One. 2023 Sep 1;18(9):e0290685. doi: 10.1371/journal.pone.0290685. eCollection 2023.
β3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the β3-AR agonists vibegron, mirabegron, solabegron, and ritobegron; however, the selectivities of these agents have not been compared directly under the same experimental conditions. Moreover, the bladders of some patients express lower β3-AR densities than those of healthy individuals, and the β3-AR density might be expected to affect agonist activity. This study assessed the β3-AR selectivities of four β3-AR agonists and examined the effects of β-AR density on their pharmacological profiles. Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing three human β-AR subtypes transfected with different amounts of plasmid DNA (0.1, 0.05, 0.025 μg/well). The half-maximal effective concentration values, intrinsic activities (IAs), and β3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were calculated to assess their pharmacological profiles. The β3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were >7937-, 517-, 21.3-, and >124-fold higher than for β1-ARs, and >7937-, 496-, >362- and 28.1-fold higher than for β2-ARs, respectively, under the same experimental conditions. The IAs of mirabegron, solabegron, and ritobegron decreased in line with decreasing receptor density, while the IA of vibegron was maintained at the same level as that of the full agonist isoproterenol at various β3-AR densities. Vibegron has high β3-AR selectivity and exhibits full agonist activity, regardless of the β3-AR density. These results suggest that vibegron is a highly effective and safe drug for treating OAB.
β3-肾上腺素受体 (AR) 激动剂被用于治疗膀胱过度活动症 (OAB) 患者。β3-AR 激动剂维贝格隆、米拉贝隆、索利贝隆和利托贝隆已经获得了临床概念验证数据；然而，这些药物的选择性尚未在相同的实验条件下直接比较。此外，一些患者的膀胱表达的β3-AR 密度低于健康个体，并且β3-AR 密度可能会影响激动剂的活性。本研究评估了四种β3-AR 激动剂的β3-AR 选择性，并研究了β-AR 密度对其药理学特征的影响。使用转染了不同量质粒 DNA（0.1、0.05、0.025μg/孔）的表达三种人类β-AR 亚型的中国仓鼠卵巢-K1 细胞进行功能性细胞测定。计算 vibegron、米拉贝隆、索利贝隆和利托贝隆的半最大有效浓度值、内在活性（IA）和β3-AR 选择性，以评估其药理学特征。在相同的实验条件下，vibegron、米拉贝隆、索利贝隆和利托贝隆对β3-AR 的选择性分别比β1-AR 高>7937、517、21.3 和>124 倍，比β2-AR 高>7937、496、>362 和 28.1 倍。在不同的β3-AR 密度下，米拉贝隆、索利贝隆和利托贝隆的 IA 随受体密度的降低而降低，而 vibegron 的 IA 则保持与完全激动剂异丙肾上腺素相同的水平。Vibegron 具有高β3-AR 选择性，并且表现出完全激动剂活性，无论β3-AR 密度如何。这些结果表明 vibegron 是治疗 OAB 的一种高效且安全的药物。
