Highly Potent and Selective Fluorescent Antagonists of the Human Adenosine A3 Receptor Based on the 1,2,4-Triazolo[4,3-a]quinoxalin-1-one Scaffold

详细信息    查看全文

• 作者：Andrea J. Vernall ; Leigh A. Stoddart ; Stephen J. Briddon ; Stephen J. Hill ; Barrie Kellam
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1771-1782
• 全文大小：548K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

The adenosine-A₃ receptor (A₃AR) is a G protein-coupled receptor that shows promise as a therapeutic target for cancer, glaucoma, and various autoimmune inflammatory disorders, and as such, there is a need for molecular probes to study this receptor. Here, we report a series of fluorescent ligands containing different linkers and fluorophores based around a 1,2,4-triazolo[4,3-a]quinoxalin-1-one antagonist. One of these conjugates (19) displayed high affinity for the A₃AR (pK_D = 9.36 卤 0.12) and is >650-fold selective over other adenosine receptor subtypes. Confocal microscopy revealed clear, displaceable membrane labeling of CHO-A₃ cells with 19, with no detectable labeling of CHO-A₁ cells under identical conditions. This fluorescent ligand was also able to specifically label the A₃AR in HEK293T cells containing a mixed adenosine receptor population. The subtype specificity, along with its excellent imaging properties, make 19 an ideal tool for studying A₃AR distribution and organization, particularly in the presence of other adenosine receptor subtypes.