Chicca Andrea, Bátora Daniel, Ullmer Christoph, Caruso Antonello, Grüner Sabine, Fingerle Jürgen, Hartung Thomas, Degen Roland, Müller Matthias, Grether Uwe, Pacher Pal, Gertsch Jürg
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern 3012, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern 3012, Switzerland.
ACS Pharmacol Transl Sci. 2024 Jul 9;7(8):2424-2438. doi: 10.1021/acsptsci.4c00269. eCollection 2024 Aug 9.
The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation , optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency ( 0.13-1.81 nM, depending on species) and a peripherally restricted action due to -glycoprotein-mediated efflux from the brain. H and C labeled RNB-61 showed apparent values of <4 nM toward human CB2R in both cell and tissue experiments. The 6,800-fold selectivity over CB1 receptors and negligible off-targets , combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical studies with superior biophysical and PK properties over generally used CB2R ligands.
大麻素CB2受体（CB2R）是不同形式的组织损伤和炎症性疾病的潜在治疗靶点。为了全面研究CB2R在病理生理条件下的作用并进行靶点验证，最佳的药理学工具化合物至关重要。尽管在生成强效和选择性CB2R配体方面取得了相当大的进展，但药代动力学参数在研究中常常被忽视。在此，我们报告了一种名为RNB-61的四取代吡唑CB2R完全激动剂的生成和特性，其具有高效力（根据物种不同，为0.13 - 1.81 nM），并且由于糖蛋白介导的从脑内流出而具有外周限制作用。在细胞和组织实验中，H和C标记的RNB-61对人CB2R的表观值均<4 nM。对CB1受体具有6800倍的选择性且脱靶效应可忽略不计，再加上高口服生物利用度和合适的全身药代动力学（PK）特性，促使我们在急性肾损伤（AKI）的小鼠缺血再灌注模型以及单侧输尿管梗阻诱导的慢性肾损伤/炎症和纤维化（CKI）的大鼠模型中对RNB-61进行评估。在AKI/CKI模型中，RNB-61发挥了剂量依赖性的肾保护和/或抗纤维化作用。因此，RNB-61是一种用于临床前研究的最佳CB2R工具化合物，与常用的CB2R配体相比，具有卓越的生物物理和PK特性。
