HU-446 and HU-465， Derivatives of the Non-psychoactive Cannabinoid Cannabidiol， Decrease the Activation of Encephalitogenic T Cells.

Cannabidiol (CBD)， the non-psychoactive cannabinoid， has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8，9-dihydro-7-hydroxy-CBD; HU-446) and of synthetic (+)-CBD ((+)-8，9-dihydro-7-hydroxy-CBD; HU-465) on activated myelin oligodendrocyte glycoprotein (MOG)35-55-specific mouse encephalitogenic T cells (T(MOG) ) driving EAE/MS-like pathologies. Binding assays followed by molecular modeling revealed that HU-446 has negligible affinity toward the cannabinoid CB1 and CB2 receptors while HU-465 binds to both CB1 and CB2 receptors at the high nanomolar concentrations (Ki = 76.7 ± 5.8 nm and 12.1 ± 2.3 nm， respectively). Both， HU-446 and HU-465， at 5 and 10 μm (but not at 0.1 and 1 μm)， inhibited the MOG35-55-induced proliferation of autoreactive T(MOG) cells via CB1/CB2 receptor independent mechanisms. Moreover， both HU-446 and HU-465， at 5 and 10 μm， inhibited the release of IL-17， a key autoimmune cytokine， from MOG35-55-stimulated T(MOG) cells. These results suggest that HU-446 and HU-465 have anti-inflammatory potential in inflammatory and autoimmune diseases.