HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

J Pharmacol Exp Ther. 2015 Oct;355(1):66-75. doi: 10.1124/jpet.115.226100. Epub 2015 Aug 13.


Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ(9)-tetrahydrocannabinol (Δ(9)-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ(9)-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ(9)-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ(9)-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemistry
  • Acetates / metabolism
  • Acetates / pharmacology*
  • Acetates / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Arthritis, Experimental / drug therapy
  • Cannabidiol / chemistry
  • Cannabidiol / metabolism
  • Cannabidiol / pharmacology*
  • Cannabidiol / therapeutic use
  • Concanavalin A / adverse effects
  • Cyclohexanecarboxylic Acids / chemistry
  • Cyclohexanecarboxylic Acids / metabolism
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Cyclohexanecarboxylic Acids / therapeutic use
  • Cytoprotection / drug effects
  • Female
  • Liver / cytology
  • Liver / drug effects
  • Liver / injuries
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Nitric Oxide / biosynthesis
  • Reactive Oxygen Species / metabolism
  • Receptors, Cannabinoid / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Acetates
  • Anti-Inflammatory Agents
  • Cyclohexanecarboxylic Acids
  • HU-444
  • Reactive Oxygen Species
  • Receptors, Cannabinoid
  • Tumor Necrosis Factor-alpha
  • Concanavalin A
  • Cannabidiol
  • Nitric Oxide