Peripheral, but not central effects of cannabidiol derivatives: Mediation by CB1 and unidentified receptors

Abstract Delta-9 tetrahydrocannabinol (Δ 9 -THC) and (−)-cannabidiol ((−)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Δ 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.