HU‐446 and HU‐465, Derivatives of the Non‐psychoactive Cannabinoid Cannabidiol, Decrease the Activation of Encephalitogenic T Cells. (16th September 2015)

• Record Type: Journal Article
• Authors: Kozela, Ewa; Haj, Christeene; Hanuš, Lumir; Chourasia, Mukesh; Shurki, Avital; Juknat, Ana; Kaushansky, Nathali; Mechoulam, Raphael; Vogel, Zvi
• Is Part Of: Chemical biology & drug design. Volume 87:Number 1(2016)
• Page Start: 143
• Page End: 153
• Publication Date: 2015-09-16
• Subjects: cannabidiol derivatives -- encephalitogenic T cells -- HU‐446 -- HU‐465 -- IL‐17 -- Th17; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12637
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : 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 (TMOG ) 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 ( K i = 76.7 ± 5.8 nm and 12.1 ± 2.3 nm, respectively). Both, HU‐446 and HU‐465, at 5 and 10 μ m (but not at 0.1 and 1 μ m ), inhibited the MOG35‐55‐induced proliferation of autoreactive TMOG cells via CB1/CB2 receptor independent mechanisms. Moreover, both HU‐446 and HU‐465, at 5 and 10 μ m, inhibited the release of IL‐17, a key autoimmune cytokine, from MOG35‐55‐stimulated TMOG cells. These results suggest that HU‐446 and HU‐465 have anti‐inflammatory potential in inflammatory and autoimmune diseases. Abstract : The study describes the synthesis and the anti‐inflammatory activities of two derivatives of the non‐psychoactive cannabinoid, cannabidiol (CBD): HU‐446 and HU‐465 ((−)‐ and (+)‐8, 9‐dihydro‐7‐hydroxy‐CBD, respectively). HU‐446 is a derivative of the natural (−)‐CBD with negligible affinity towards CB1 or CB2 receptors while HU‐465, a derivative of synthetic (+)‐CBD, is capable of interacting with both. HU‐446 and HU‐465 decrease the in vitro activation of encephalitogenic T cells by MOG35‐55, including their proliferation and IL‐17 release, a key autoimmune cytokine.