FLUORINATED CANNABINOID CB2 RECEPTOR LIGANDS: SYNTHESIS AND IN VITRO BINDING CHARACTERISTICS OF 2-OXOQUINOLINE DERIVATIVES

摘要

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, >13-16 18, 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 [³H]CP-55,940 in U87hCB1 and U87hCB2 cells. Inhibition constant (Ki) values of compounds >13, 14, 15, 16, 18, 19, 21, 22, 23, 24, 27, and >28 for CB2 were >10000, 2.8, 5.0, 2.4, 22, 0.8, 1.4, >10000, 486, 58, 620, and 2400 nM, respectively, and those for CB1 were >10000 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 Ki value, could be radiolabeled with ¹⁸F and explored for PET imaging of CB2 expression.