A highly potent, orally bioavailable pyrazole-derived cannabinoid CB2 receptor-selective full agonist for in vivo studies
A highly potent, orally bioavailable pyrazole-derived cannabinoid CB2 receptor-selective full agonist for in vivo studies
Abstract 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 in vivo, 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 in vivo studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency (Ki 0.13–1.81 nM, depending on species) and a peripherally restricted action due to P-glycoprotein mediated efflux from the brain. 3H and 14C labelled RNB-61 showed apparent Kd values < 4 nM towards human CB2R in both cell and tissue experiments. The >6000-fold selectivity over CB1 receptors and negligible off-targets in vitro, 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 in vivo studies with superior biophysical and PK properties over generally used CB2R ligands.
Batora Daniel、Ullmer Christoph、Hartung Thomas、Degen Roland、Grether Uwe、Pacher Pal、Chicca Andrea、M¨1ller Matthias、Fingerle J¨1rgen、Caruso Antonello、Gertsch J¨1rg
Institute of Biochemistry and Molecular Medicine, University of Bern||Graduate School for Cellular and Biomedical Sciences, University of BernPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentLaboratory of Cardiovascular Physiology and Tissue Injury (P.P.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIH)Institute of Biochemistry and Molecular Medicine, University of BernPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentPharmaceutical Sciences, Roche Innovation Center Basel, Roche Pharma Research and Early DevelopmentInstitute of Biochemistry and Molecular Medicine, University of Bern
药学基础医学生物科学研究方法、生物科学研究技术
Batora Daniel,Ullmer Christoph,Hartung Thomas,Degen Roland,Grether Uwe,Pacher Pal,Chicca Andrea,M¨1ller Matthias,Fingerle J¨1rgen,Caruso Antonello,Gertsch J¨1rg.A highly potent, orally bioavailable pyrazole-derived cannabinoid CB2 receptor-selective full agonist for in vivo studies[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2024.04.26.591311.点此复制
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