Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors

Neuropharmacology. 2005 Jun;48(8):1117-29. doi: 10.1016/j.neuropharm.2005.01.023. Epub 2005 Apr 26.


Delta-9 tetrahydrocannabinol (Delta(9)-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Delta(9)-THC activates cannabinoid CB(1) and CB(2) receptors and induces psychoactive and peripheral effects. (-)-CBD possesses no, or very weak affinity for these receptors. We tested a series of (+)- and (-)-CBD derivatives for central and peripheral effects in mice. None of the (-)-CBD derivatives were centrally active, yet most inhibited intestinal motility. Of the five (+)-CBD derivatives, all with CB(1) receptor affinity, only (+)-7-OH-CBD-DMH (DMH=1,1-dimethylheptyl), acted centrally, while all five arrested defecation. The effects of (+)-CBD-DMH and (+)-7-OH-CBD-DMH were inhibited by the CB(1) receptor antagonist SR141716. The CB(2) receptor antagonist SR144528, and the vanilloid TRPV1 receptor antagonist capsazepine, had no influence. Further, the (-)-CBD derivatives (-)-7-COOH-CBD and (-)-7-COOH-CBD-DMH, displayed antiinflammatory activity. We suggest that (+)-CBD analogues have mixed agonist/antagonist activity in the brain. Second, (-)-CBD analogues which are devoid of cannabinoid receptor affinity but which inhibit intestinal motility, suggest the existence of a non-CB(1), non-CB(2) receptor. Therefore, such analogues should be further developed as antidiarrheal and/or antiinflammatory drugs. We propose to study the therapeutic potential of (-)- and (+)-CBD derivatives for complex conditions such as inflammatory bowel disease and cystic fibrosis.

MeSH terms

  • Animals
  • Binding, Competitive
  • Body Temperature / drug effects*
  • Camphanes / pharmacology
  • Cannabidiol / analogs & derivatives*
  • Cannabidiol / pharmacology*
  • Cannabidiol / therapeutic use
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology
  • Drug Interactions
  • Ear, External
  • Gastrointestinal Motility / drug effects*
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Mice
  • Mice, Inbred ICR
  • Mice, Inbred Strains
  • Motor Activity / drug effects*
  • Pain Measurement / drug effects*
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Rimonabant


  • Camphanes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • SR 144528
  • Cannabidiol
  • capsazepine
  • Rimonabant
  • Capsaicin