Andrea Chicca, Daniel Bátora, Christoph Ullmer, Antonello Caruso, Sabine Grüner, Jürgen Fingerle, Thomas Hartung, Roland Degen, Matthias Müller, Uwe Grether, Pal Pacher, Jürg Gertsch
{"title":"A Highly Potent, Orally Bioavailable Pyrazole-Derived Cannabinoid CB2 Receptor- Selective Full Agonist for In Vivo Studies","authors":"Andrea Chicca, Daniel Bátora, Christoph Ullmer, Antonello Caruso, Sabine Grüner, Jürgen Fingerle, Thomas Hartung, Roland Degen, Matthias Müller, Uwe Grether, Pal Pacher, Jürg Gertsch","doi":"10.1021/acsptsci.4c00269","DOIUrl":null,"url":null,"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 <i>in vivo</i>, 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 <i>in vivo</i> studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency (<i>K</i><sub>i</sub> 0.13–1.81 nM, depending on species) and a peripherally restricted action due to <i>P</i>-glycoprotein-mediated efflux from the brain. <sup>3</sup>H and <sup>14</sup>C labeled RNB-61 showed apparent <i>K</i><sub>d</sub> 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 <i>in vitro</i>, 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 <i>in vivo</i> studies with superior biophysical and PK properties over generally used CB2R ligands.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Pharmacology & Translational Science","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1021/acsptsci.4c00269","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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 labeled RNB-61 showed apparent Kd 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 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.