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

doi:10.1124/mol.63.3.699

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Vol. 63, Issue 3, 699-705, March 2003

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

László Offertáler, Fong-Ming Mo, Sándor Bátkai, Jie Liu, Malcolm Begg, Raj K. Razdan, Billy R. Martin, Richard D. Bukoski, and George Kunos

Laboratory of Physiologic Studies, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, Maryland (L.O., S.B., J.L., M.B., G.K.); Organix, Inc., Woburn, Massachusetts (R.K.R.); Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (B.R.M.); and Cardiovascular Disease Research Program, North Carolina Central University, Durham, North Carolina (R.D.B.)

The cannabinoid analog abnormal cannabidiol [abn-cbd; ( $-$ )-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind toCB₁ or CB₂ receptors, yet it acts as a full agonist in relaxingrat isolated mesenteric artery segments. Vasorelaxation by abn-cbdis endothelium-dependent, pertussis toxin-sensitive, and is inhibitedby the BK_Ca channel inhibitor charybdotoxin, but not by the nitric-oxidesynthase inhibitor N-nitro-L-arginine methyl ester or by the vanilloid VR1 receptorantagonist capsazepine. The cannabidiol analog O-1918 does notbind to CB₁ or CB₂ receptors and does not cause vasorelaxationat concentrations up to 30 µM, but it does cause concentration-dependent(1-30 µM) inhibition of the vasorelaxant effects of abn-cbd andanandamide. In anesthetized mice, O-1918 dose-dependently inhibitsthe hypotensive effect of abn-cbd but not the hypotensive effectof the CB₁ receptor agonist ( $-$ )-11-OH- $Delta$ ⁹-tetrahydrocannabinol dimethylheptyl. In human umbilical veinendothelial cells, abn-cbd induces phosphorylation of p42/44 mitogen-activatedprotein kinase and protein kinase B/Akt, which is inhibited byO-1918, by pertussis toxin or by phosphatidylinositol 3 (PI3)kinase inhibitors. These findings indicate that abn-cbd is a selectiveagonist and that O-1918 is a selective, silent antagonist of anendothelial "anandamide receptor", which is distinct from CB₁or CB₂ receptors and is coupled through G_i/G_o to the PI3 kinase/Aktsignalingpathway.

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