• DOI:10.1124/MOL.63.3.699
• Corpus ID: 30793949

Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor.

@article{Offertler2003SelectiveLA,
  title={Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor.},
  author={L{\'a}szl{\'o} Offert{\'a}ler and Fong Ming Mo and Sandor Batkai and Jie Liu and Malcolm Begg and Raj Kumar Razdan and Billy R. Martin and Richard D. Bukoski and George Kunos},
  journal={Molecular pharmacology},
  year={2003},
  volume={63 3},
  pages={
          699-705
        }
}

• László Offertáler, F. Mo, +6 authors G. Kunos
• Published 1 March 2003
• Biology, Chemistry, Medicine
• Molecular pharmacology

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(omega)-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 microM, but it does cause concentration-dependent (1-30 microM) 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-Delta(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.