adenosine-5--(n-ethylcarboxamide) and Glioblastoma

Adenosine induces glioma cell proliferation by means of an antiapoptotic effect, which is blocked by cotreatment with selective A(3) AR antagonists. In this study, a novel series of N(2)-substituted pyrazolo[3,4-d]pyrimidines 2a-u was developed as highly potent and selective A(3) AR antagonists. The most performing compounds were derivatives 2a (R(1) = CH(3) and R(2) = COC(6)H(5); K(i) 334, 728, and 0.60 nM at the human A(1), A(2A), and A(3) ARs, respectively) and 2b (R(1) = CH(3) and R(2) = COC(6)H(4)-4-OCH(3); K(i) 1037, 3179, and 0.18 nM at the human A(1), A(2A), and A(3) ARs, respectively), which counteracted the effect of the A(3) AR agonists Cl-IB-MECA and IB-MECA on human glioma U87MG cell proliferation. This effect was concentration-dependent, with IC(50) values comparable to A(3) AR binding affinity values of 2a and 2b, thereby suggesting that their effects were receptor-mediated. Furthermore, the antiproliferative activity of the new compounds was demonstrated to be mediated by the block of A(3) AR agonist activation of intracellular kinases ERK 1/2.

Topics: Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Animals; Antineoplastic Agents; Binding, Competitive; Cell Line, Tumor; Cell Proliferation; Chemotherapy, Adjuvant; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Enzyme Activation; Glioblastoma; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Molecular; Phosphorylation; Pyrazoles; Pyrimidines; Radioligand Assay; Structure-Activity Relationship