title: (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only.
abstract: Delta9-Tetrahydrocannabinol (Delta9-THC) and (-)-cannabidiol are major constituents of the Cannabis sativa plant with different pharmacological profiles: (-)-Delta9-tetrahydrocannabinol, but not (-)-cannabidiol, activates cannabinoid CB1 and CB2 receptors and induces psychoactive and peripheral effects. We have tested a series of (+)-cannabidiol derivatives, namely, (+)-cannabidiol-DMH (DMH-1,1-dimethylheptyl-), (+)-7-OH-cannabidiol-DMH, (+)-7-OH- cannabidiol, (+)-7-COOH- cannabidiol and (+)-7-COOH-cannabidiol-DMH, for central and peripheral (intestinal, antiinflammatory and peripheral pain) effects in mice. Although all (+)-cannabidiols bind to cannabinoid CB1 and CB2 receptors, only (+)-7-OH-cannabidiol-DMH was centrally active, while all (+)-cannabidiol analogues completely arrested defecation. The effects of (+)-cannabidiol-DMH and (+)-7-OH-cannabidiol-DMH were partially antagonized by the cannabinoid CB1 receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716), but not by the cannabinoid CB2 receptor antagonist N-[-(1S)-endo-1,3,3-trimethil bicyclo [2.2.1] heptan-2-yl-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), and had no effect on CB1(-/-) receptor knockout mice. (+)-Cannabidiol-DMH inhibited the peripheral pain response and arachidonic-acid-induced inflammation of the ear. We conclude that centrally inactive (+)-cannabidiol analogues should be further developed as antidiarrheal, antiinflammatory and analgesic drugs for gastrointestinal and other peripheral conditions.
authors.affiliation: Department of Behavioral Sciences, College of Judea and Samaria, Ariel 44837, Israel. fride@research.yosh.ac.il
authors.forename: Ester
authors.initials: E
authors.lastname: Fride
authors.forename: Cfir
authors.initials: C
authors.lastname: Feigin
authors.forename: Datta E
authors.initials: DE
authors.lastname: Ponde
authors.forename: Aviva
authors.initials: A
authors.lastname: Breuer
authors.forename: Lumír
authors.initials: L
authors.lastname: Hanus
authors.forename: Nina
authors.initials: N
authors.lastname: Arshavsky
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D003672:Defecation / Q000187:drug effects; D004431:Ear, External / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005557:Formaldehyde; D005769:Gastrointestinal Motility / Q000187:drug effects; D051379:Mice; D017933:Peripheral Nervous System / Q000187:drug effects*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D002185:Cannabidiol; D005557:Formaldehyde; D016718:Arachidonic Acid