Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists.

The cannabinoid signaling system includes two G protein-coupled receptors, CB and CB 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 CB and CB are involved in diverse processes, it would be advantageous to develop ligands that differentially engage CB and CB 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 CB agonists, can antagonize CB receptor signaling. In autaptic hippocampal neurons, GW405833 and AM1710 both interfered with CB-mediated depolarization-induced suppression of excitation, with GW405833 being more potent. In addition, in CB-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 CB 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 CB/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 CB receptor, with no evident time dependence. In summary, we determined that GW405833 and AM1710 are not only CB agonists but also CB antagonists, with distinctive and complex signaling properties. Thus, experiments using these compounds must take into account their potential activity at CB receptors.