(+)-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.


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.

Keywords: (+)-enantiomers; Cannabidiol; Cannabinoid 1 receptor; Cannabinoid 2 receptor; Cannabinoids; Diabetic nephropathy; Type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cannabinoid Receptor Agonists / therapeutic use*
  • Cannabinoids / pharmacology
  • Cannabinoids / therapeutic use*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Kidney / drug effects
  • Kidney / pathology
  • Mice
  • Mice, Inbred C57BL
  • Pancreas / drug effects
  • Pancreas / pathology
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB2 / agonists*


  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2