HU-444, A Novel, Potent Anti-Inflammatory, Non-Psychotropic 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 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 TNF-α, a proinflammatory cytokine, and was found to be an oral anti-arthritic 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-a 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.

ABBREVIATIONS:

CII, type II collagen; CBD, cannabidiol; CIA, collagen-induced arthritis; Con A, Concanavalin-A; HU-444, (-)-8,9-dihydro-CBD-7-oic acid-diacetate; DMEM, Dulbecco’s modified Eagle medium; FCS, fetal calf serum; LPS, lipopolysaccharide; NO, nitric oxide; RA, rheumatoid arthritis; RPMI-1640, Roswell Park Memorial Institute-1640 medium; THC, Δ9-tetrahydrocannabinol; TG, thioglycollate elicited peritoneal macrophages; TNF-α, tumor necrosis factor alpha.
The American Society for Pharmacology and Experimental Therapeutics.