title: CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene.
abstract: The purpose of the current study was to investigate the ability of the third-generation selective estrogen receptor modulators (SERMs) bazedoxifene and lasofoxifene to bind and act on CB2 cannabinoid receptor. We have identified, for the first time, that CB2 is a novel target for bazedoxifene and lasofoxifene. Our results showed that bazedoxifene and lasofoxifene were able to compete for specific [(3)H]CP-55,940 binding to CB2 in a concentration-dependent manner. Our data also demonstrated that by acting on CB2, bazedoxifene and lasofoxifene concentration-dependently enhanced forskolin-stimulated cAMP accumulation. Furthermore, bazedoxifene and lasofoxifene caused parallel, rightward shifts of the CP-55,940, HU-210, and WIN55,212-2 concentration-response curves without altering the efficacy of these cannabinoid agonists on CB2, which indicates that bazedoxifene- and lasofoxifene-induced CB2 antagonism is most likely competitive in nature. Our discovery that CB2 is a novel target for bazedoxifene and lasofoxifene suggests that these third-generation SERMs can potentially be repurposed for novel therapeutic indications for which CB2 is a target. In addition, identifying bazedoxifene and lasofoxifene as CB2 inverse agonists also provides important novel mechanisms of actions to explain the known therapeutic effects of these SERMs.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, United States.
authors.forename: Pritesh
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, United States. Electronic address: zhsong@louisville.edu.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Song
mesh_terms: D048588:Benzoxazines / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D048588:Benzoxazines; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D011759:Pyrrolidines; D043885:Receptor, Cannabinoid, CB2; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D000242:Cyclic AMP; C447119:bazedoxifene; C062018:HU 211
keywords: Bazedoxifene; CB1; CB2; Cannabinoid receptor; FDA; G protein-coupled receptor; GPCR; HTRF; Inverse agonist; Lasofoxifene; SERM; Selective estrogen receptor modulator; cannabinoid receptor 1; cannabinoid receptor 2; food and drug administration; homogenous time resolved fluorescence; selective estrogen receptor modulator