title: Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists.
abstract: The cannabinoid signaling system includes two G protein-coupled receptors, CB1and CB2These 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 CB1and CB2are involved in diverse processes, it would be advantageous to develop ligands that differentially engage CB1and CB2We 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 CB2agonists, can antagonize CB1receptor 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 CB1internalization 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 CB1receptor, with no evident time dependence. In summary, we determined that GW405833 and AM1710 are not only CB2agonists but also CB1antagonists, with distinctive and complex signaling properties. Thus, experiments using these compounds must take into account their potential activity at CB1receptors.
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana (A.D., N.M., A.S., K.M.); and Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts (A.M.).
authors.forename: Amey
authors.initials: A
authors.lastname: Dhopeshwarkar
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana (A.D., N.M., A.S., K.M.); and Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts (A.M.).
authors.forename: Natalia
authors.initials: N
authors.lastname: Murataeva
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana (A.D., N.M., A.S., K.M.); and Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts (A.M.).
authors.forename: Alex
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana (A.D., N.M., A.S., K.M.); and Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts (A.M.) straiker@indiana.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Straiker
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana (A.D., N.M., A.S., K.M.); and Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts (A.M.).
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
mesh_terms: D000818:Animals; D019393:Arrestin / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*
chemical_list: C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; C500321:3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one; D019393:Arrestin; D002867:Chromones; D007211:Indoles; D007295:Inositol Phosphates; D009025:Morpholines; D010750:Phosphoproteins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D005576:Colforsin; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3