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00925njm 22002777a 4500 dc González-Mariscal, Isabel author Carmona-Hidalgo, Beatriz author Winkler, Matthias author Unciti-Broceta, Juan D. author Escamilla-Sánchez, Alejandro author Gómez-Cañas, María author Fernández-Ruiz, Javier author Fiebich, Bernd L. author Romero-Zerbo, Silvana Yanina author Bermúdez Silva, Francisco Javier author Collado, Juan A. author Muñoz, Eduardo author 2021-07-01 Natural cannabidiol ((-)-CBD) and its derivatives have increased interest for medicinal applications due to their broad biological activity spectrum, including targeting of the cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that showed enhanced CB1R and CB2R binding and functional activities compared to their respective (-) enantiomers. (+)-CBD-HPE Ki values for CB1R and CB2R were 3.1 ± 1.1 and 0.8 ± 0.1 nM respectively acting as CB1R antagonist and CB2R agonist. We further tested the capacity of (+)-CBD-HPE to prevent hyperglycemia and its complications in a mouse model. (+)-CBD-HPE significantly reduced streptozotocin (STZ)-induced hyperglycemia and glucose intolerance by preserving pancreatic beta cell mass. (+)-CBD-HPE significantly reduced activation of NF-κB by phosphorylation by 15% compared to STZ-vehicle mice, and CD3+ T cell infiltration into the islets was avoided. Consequently, (+)-CBD-HPE prevented STZ-induced apoptosis in islets. STZ induced inflammation and kidney damage, visualized by a significant increase in plasma proinflammatory cytokines, creatinine, and BUN. Treatment with (+)-CBD-HPE significantly reduced 2.5-fold plasma IFN-γ and increased 3-fold IL-5 levels compared to STZ-treated mice, without altering IL-18. (+)-CBD-HPE also significantly reduced creatinine and BUN levels to those comparable to healthy controls. At the macroscopy level, (+)-CBD-HPE prevented STZ-induced lesions in the kidney and voided renal fibrosis and CD3+ T cell infiltration. Thus, (+)-enantiomers of CBD, particularly (+)-CBD-HPE, have a promising potential due to their pharmacological profile and synthesis, potentially to be used for metabolic and immune-related disorders. González-Mariscal I, Carmona-Hidalgo B, Winkler M, Unciti-Broceta JD, Escamilla A, Gómez-Cañas M, Fernández-Ruiz J, Fiebich BL, Romero-Zerbo SY, Bermúdez-Silva FJ, Collado JA, Muñoz E. (+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice. Pharmacol Res. 2021 Jul;169:105492. doi: 10.1016/j.phrs.2021.105492. Epub 2021 May 19. PMID: 34019978. https://hdl.handle.net/10630/36161 10.1016/j.phrs.2021.105492 Histología (+)-trans-Cannabidiol-2-hydroxy pentyl is a dual CB1R antagonist/CB2R agonist that prevents diabetic nephropathy in mice