HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid.
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.
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.).
Christeene G
CG
Haj
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.).
Percy F
PF
Sumariwalla
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.).
Lumír
L
Hanuš
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.).
Natalya M
NM
Kogan
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.).
Zhana
Z
Yektin
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.
Raphael
R
Mechoulam
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.).
Mark
M
Feldmann
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.
Ruth
R
Gallily
D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D002185:Cannabidiol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003208:Concanavalin A / Q000009:adverse effects; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D019610:Cytoprotection / Q000187:drug effects; D005260:Female; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000293:injuries; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000085:Acetates; D000893:Anti-Inflammatory Agents; D003509:Cyclohexanecarboxylic Acids; C000602675:HU-444; D017382:Reactive Oxygen Species; D043882:Receptors, Cannabinoid; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D002185:Cannabidiol; D009569:Nitric Oxide