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

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

Author information

1
Institute for Drug Research (C.G.H., L.H., N.M.K., R.M.) and Lautenberg Center for Immunology (Z.Y., R.G.), Hebrew University Medical Faculty, Jerusalem, Israel; and Kennedy Institute of Rheumatology, Hammersmith, London, United Kingdom (P.F.S., M.F.).
2
Institute for Drug Research (C.G.H., L.H., N.M.K., R.M.) and Lautenberg Center for Immunology (Z.Y., R.G.), Hebrew University Medical Faculty, Jerusalem, Israel; and Kennedy Institute of Rheumatology, Hammersmith, London, United Kingdom (P.F.S., M.F.) mechou@cc.huji.ac.il ruthg@ekmd.huji.ac.il.

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 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.

PMID:
26272937
PMCID:
PMC4576666
DOI:
10.1124/jpet.115.226100
[Indexed for MEDLINE]
Free PMC Article

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