Journal
MOLECULAR PHARMACOLOGY
Volume 63, Issue 3, Pages 699-705Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.63.3.699
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The cannabinoid analog abnormal cannabidiol [abn-cbd; (-) 4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB1 or CB2 receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive, and is inhibited by the BKCa channel inhibitor charybdotoxin, but not by the nitric-oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester or by the vanilloid VR1 receptor antagonist capsazepine. The cannabidiol analog O-1918 does not bind to CB1 or CB2 receptors and does not cause vasorelaxation at concentrations up to 30 muM, but it does cause concentration-dependent (1-30 muM) inhibition of the vasorelaxant effects of abn-cbd and anandamide. In anesthetized mice, O-1918 dose-dependently inhibits the hypotensive effect of abn-cbd but not the hypotensive effect of the CB1 receptor agonist (-)-11-OH-Delta(9)-tetrahydro-cannabinol dimethylheptyl. In human umbilical vein endothelial cells, abn-cbd induces phosphorylation of p42/44 mitogen-activated protein kinase and protein kinase B/Akt, which is inhibited by O-1918, by pertussis toxin or by phosphatidylinositol 3 (PI3) kinase inhibitors. These findings indicate that abn-cbd is a selective agonist and that O-1918 is a selective, silent antagonist of an endothelial anandamide receptor, which is distinct from CB1 or CB2 receptors and is coupled through G(i)/G(o) to the PI3 kinase/Akt signaling pathway.
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