The cannabinoid analog abnormal cannabidiol [abn-cbd; (Ϫ)-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 abncbd 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 -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 M, but it does cause concentration-dependent (1-30 M) 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 (Ϫ)-11-OH-⌬ 9 -tetrahydrocannabinol dimethylheptyl. In human umbilical vein endothelial cells, abn-cbd induces phosphorylation of p42/44 mitogenactivated 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 abncbd 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.