title: Fluorinated cannabinoid CB2 receptor ligands: synthesis and in vitro binding characteristics of 2-oxoquinoline derivatives.
abstract: Cannabinoid receptor 2 (CB2) plays an important role in human physiology and the pathophysiology of different diseases, including neuroinflammation, neurodegeneration, and cancer. Several classes of CB2 receptor ligands, including 2-oxoquinoline derivatives, have been previously reported. We report the synthesis and results of in vitro receptor binding of a focused library of new fluorinated 2-oxoquinoline CB2 ligands. Twelve compounds, 13-1618, 19, 21-24, 27, and 28 were synthesized in good yields in multiple steps. Human U87 glioma cells expressing either hCB1 (control) or hCB2 were generated via lentiviral transduction. In vitro competitive binding assay was performed using [(3)H]CP-55,940 in U87hCB1 and U87hCB2 cells. Inhibition constant (K(i)) values of compounds 13-16, 18, 19, 21-24, 27, and 28 for CB2 were >10,000, 2.8, 5.0, 2.4, 22, 0.8, 1.4, >10,000, 486, 58, 620, and 2400 nM, respectively, and those for CB1 were >10,000 nM. Preliminary in vitro results suggest that six of these compounds may be useful for therapy of neuropathic pain, neuroinflammatory diseases and immune disorders. In addition, compound 19, with its subnanomolar K(i) value, could be radiolabeled with (18)F and explored for PET imaging of CB2 expression.
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas, M D Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Nashaat
authors.initials: N
authors.lastname: Turkman
authors.forename: Aleksander
authors.initials: A
authors.lastname: Shavrin
authors.forename: Roman A
authors.initials: RA
authors.lastname: Ivanov
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.forename: Andrei
authors.initials: A
authors.lastname: Volgin
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D015363:Quinolones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2