Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists

The cannabinoid signaling system includes two G protein-coupled receptors, CB₁ and CB₂ These receptors are widely distributed throughout the body and have each been implicated in many physiologically important processes. Although the cannabinoid signaling system has therapeutic potential, the development of receptor-selective ligands remains a persistent hurdle. Because CB₁ and CB₂ are involved in diverse processes, it would be advantageous to develop ligands that differentially engage CB₁ and CB₂ We now report that GW405833 [1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole] and AM1710 [1-hydroxy-9-methoxy-3-(2-methyloctan-2-yl)benzo[c]chromen-6-one], described as selective CB₂ agonists, can antagonize CB₁ receptor signaling. In autaptic hippocampal neurons, GW405833 and AM1710 both interfered with CB₁-mediated depolarization-induced suppression of excitation, with GW405833 being more potent. In addition, in CB₁-expressing human embryonic kidney 293 cells, GW405833 noncompetitively antagonized adenylyl cyclase activity, extracellular signal-regulated kinase 1/2 phosphorylation, phosphatidylinositol 4,5-bisphosphate signaling, and CB₁ internalization by CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol). In contrast, AM1710 behaved as a low-potency competitive antagonist/inverse agonist in these signaling pathways. GW405833 interactions with CB₁/arrestin signaling were complex: GW405833 differentially modulated arrestin recruitment in a time-dependent fashion, with an initial modest potentiation at 20 minutes followed by antagonism starting at 1 hour. AM1710 acted as a low-efficacy agonist in arrestin signaling at the CB₁ receptor, with no evident time dependence. In summary, we determined that GW405833 and AM1710 are not only CB₂ agonists but also CB₁ antagonists, with distinctive and complex signaling properties. Thus, experiments using these compounds must take into account their potential activity at CB₁ receptors.