TY - JOUR T1 - HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 66 LP - 75 DO - 10.1124/jpet.115.226100 VL - 355 IS - 1 AU - Christeene G. Haj AU - Percy F. Sumariwalla AU - Lumír Hanuš AU - Natalya M. Kogan AU - Zhana Yektin AU - Raphael Mechoulam AU - Mark Feldmann AU - Ruth Gallily Y1 - 2015/10/01 UR - http://jpet.aspetjournals.org/content/355/1/66.abstract N2 - 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 Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-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 Δ9-THC–like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases. ER -