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

Ewa Kozela*, Christeene Haj, Lumir Hanuš, Mukesh Chourasia, Avital Shurki, Ana Juknat, Nathali Kaushansky, Raphael Mechoulam, Zvi Vogel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 (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 TMOG 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 TMOG cells. These results suggest that HU-446 and HU-465 have anti-inflammatory potential in inflammatory and autoimmune diseases.

Original languageAmerican English
Pages (from-to)143-153
Number of pages11
JournalChemical Biology and Drug Design
Volume87
Issue number1
DOIs
StatePublished - 1 Jan 2016

Bibliographical note

Publisher Copyright:
© 2015 John Wiley & Sons A/S.

Keywords

  • HU-446
  • HU-465
  • IL-17
  • Th17
  • cannabidiol derivatives
  • encephalitogenic T cells

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