TY - JOUR
T1 - Peripheral, but not central effects of cannabidiol derivatives
T2 - Mediation by CB1 and unidentified receptors
AU - Fride, Ester
AU - Ponde, Datta
AU - Breuer, Aviva
AU - Hanuš, Lumir
PY - 2005/6
Y1 - 2005/6
N2 - Delta-9 tetrahydrocannabinol (Δ9-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Δ9-THC activates cannabinoid CB 1 and CB2 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 CB1 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 CB2 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-CB1, 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.
AB - Delta-9 tetrahydrocannabinol (Δ9-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Δ9-THC activates cannabinoid CB 1 and CB2 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 CB1 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 CB2 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-CB1, 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.
KW - Cannabidiol
KW - CB receptors
KW - CB receptors
KW - Inflammation
KW - Intestinal motility
KW - Vanilloid TRPV1 receptors
UR - http://www.scopus.com/inward/record.url?scp=19444387559&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2005.01.023
DO - 10.1016/j.neuropharm.2005.01.023
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C2 - 15910887
AN - SCOPUS:19444387559
SN - 0028-3908
VL - 48
SP - 1117
EP - 1129
JO - Neuropharmacology
JF - Neuropharmacology
IS - 8 SPEC. ISS.
ER -