Selective Ligands and Cellular Effectors of a G Protein-Coupled Endothelial Cannabinoid Receptor

The cannabinoid analog abnormal cannabidiol [abn-cbd; (−)-4-(3–3,4- trans - p -menthadien-[1,8]-yl)-olivetol] does not bind to CB 1 or CB 2 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 BK Ca channel inhibitor charybdotoxin, but not by the nitric-oxide synthase inhibitor N ω -nitro- l -arginine methyl ester or by the vanilloid VR1 receptor antagonist capsazepine. The cannabidiol analog O-1918 does not bind to CB 1 or CB 2 receptors and does not cause vasorelaxation at concentrations up to 30 μM, but it does cause concentration-dependent (1–30 μM) 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 CB 1 receptor agonist (−)-11-OH-Δ 9 -tetrahydrocannabinol 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 CB 1 or CB 2 receptors and is coupled through G i /G o to the PI3 kinase/Akt signaling pathway.