Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors.
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.
Fride
Ester
E
Department of Behavioral Sciences, College of Judea and Samaria, Ariel 44837, Israel; Department of Molecular Biology, College of Judea and Samaria, Ariel 44837, Israel. fride@research.yosh.ac.il
Ponde
Datta
D
Breuer
Aviva
A
Hanus
Lumir
L
D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects*; D001892:Camphanes / Q000494:pharmacology; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004431:Ear, External; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant
D001892:Camphanes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D002185:Cannabidiol; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin