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

Abstract

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 D 9 -tetrahydrocannabinol (D 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)-a, 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 D 9 -THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a D 9-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-a and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause D 9-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

“…Actually, new CBD-derived molecules aimed at improving the efficacy and/or potency of natural phytocannabinoids have been recently developed (Haj et al, 2015; Breuer et al, 2016). …”

Cannabinoids in liver diseases

“…Although the first CB ligands, such as rimonabant, were effective, they were also encumbered with significant toxicity; novel compounds with improved specificity, restricted to the organ of interest and lacking neuropsychiatric adverse effects, are needed and are currently being developed. Some of them, such as AM6545, TM38837, and HU‐444, have entered clinical testing …”

Medical cannabis: Another piece in the mosaic of autoimmunity?

“…An immunosuppressive effect is also achieved using synthetic cannabinoids. HU‐444, a nonpsychotropic synthetic cannabinoid, inhibits up to 69% TNF‐α production by macrophages stimulated by lipopolysaccharide (LPS) and 62% decrease of reactive oxygen species generation in macrophages stimulated by zymosan . An additional nonpsychotropic synthetic cannabinoid named ajulemic acid exhibits an immunosuppressive effect as well.…”

“…HU-444, a nonpsychotropic synthetic cannabinoid, inhibits up to 69% TNF-a production by macrophages stimulated by lipopolysaccharide (LPS) and 62% decrease of reactive oxygen species generation in macrophages stimulated by zymosan. 27 An additional nonpsychotropic synthetic cannabinoid named ajulemic acid exhibits an immunosuppressive effect as well. Monocyte derived macrophages stimulated with LPS treated with ajulemic acid showed a 69% decrease in IL-6 release with a compatible reduction in IL-6 gene expression.…”