TY - JOUR
T1 - Fluorinated cannabinoid CB2 receptor ligands
T2 - Synthesis and in vitro binding characteristics of 2-oxoquinoline derivatives
AU - Turkman, Nashaat
AU - Shavrin, Aleksander
AU - Ivanov, Roman A.
AU - Rabinovich, Brian
AU - Volgin, Andrei
AU - Gelovani, Juri G.
AU - Alauddin, Mian M.
N1 - Funding Information:
This work was supported by the Developmental Projects Program of the Center for Advanced Biomedical Imaging Research (CABIR) at MD Anderson Cancer Center, and grants: 1 U24 CA126577 01 (NIH) and CA 106672 (NIH).
PY - 2011/9/15
Y1 - 2011/9/15
N2 - 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 (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 18F and explored for PET imaging of CB2 expression.
AB - 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 (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 18F and explored for PET imaging of CB2 expression.
KW - Cannabinoid receptor 2
KW - Central nervous system
KW - Multiple sclerosis
KW - Neurodegeneration
KW - Neuroinflammation
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U2 - 10.1016/j.bmc.2011.07.062
DO - 10.1016/j.bmc.2011.07.062
M3 - Article
C2 - 21872477
AN - SCOPUS:80052604108
SN - 0968-0896
VL - 19
SP - 5698
EP - 5707
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 18
ER -