Bitopic fluorescent antagonists of the A2A adenosine receptor based on pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine functionalized congeners,RSC Medicinal Chemistry

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Bitopic fluorescent antagonists of the A2A adenosine receptor based on pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine functionalized congeners
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-06-22 00:00:00 , DOI: 10.1039/c7md00247e
Romain Duroux _{1,

2,

3,

4,

5} , Antonella Ciancetta _{1,

2,

3,

4,

5} , Philip Mannes _{1,

2,

3,

4,

5} , Jinha Yu _{1,

2,

3,

4,

5} , Shireesha Boyapati _{1,

2,

3,

4,

5} , Elizabeth Gizewski _{6,

7,

8,

9} , Said Yous _{10,

11,

12,

13,

14} , Francisco Ciruela _{15,

16,

17,

18,

19} , John A. Auchampach _{6,

7,

8,

9} , Zhan-Guo Gao _{1,

2,

3,

4,

5} , Kenneth A. Jacobson _{1,

2,

3,

4,

5}

Affiliation

Molecular Recognition Section
Laboratory of Bioorganic Chemistry
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda
Department of Pharmacology
Medical College of Wisconsin
Milwaukee
USA
Inserm
CHU Lille
UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer
Univ. Lille
F-59000 Lille
Unitat de Farmacologia, Departament Patologia i Terapeutica Experimental
Facultat de Medicina
IDIBELL
Universitat de Barcelona
08907 L'Hospitalet de Llobregat

A pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine antagonist of the A_2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A_2AAR binding modes were predicted computationally. The optimal n-butyl spacer was incorporated into the following A_2AAR-selective (K_i, nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA_2AAR-expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A_2AAR antagonists. Water-soluble sulfonate 13 was a highly potent (K_i = 6.2 nM) and selective A_2AAR antagonist based on binding and functional assays. Docking and molecular dynamics simulations predicted the regions of interaction of the distal portions of these chain-extended ligands with the A_2AAR. The BODIPY630/650 fluorophore of 11 was buried in a hydrophobic interhelical (TM1/TM7) region, while AlexaFluor488 of 12 associated with the hydrophilic extracellular loops. In conclusion, we have identified novel high affinity antagonist probes for A_2AAR drug discovery and characterization.

中文翻译：

基于吡唑并[4,3- e ] [1,2,4]三唑并[1,5 - c ]嘧啶-5-胺官能化同源物的A _2A腺苷受体的双位荧光拮抗剂

A _2A腺苷受体（AR）的吡唑并[4,3- e ] [1,2,4]三唑并[1,5 - c ]嘧啶-5-胺拮抗剂被官能化为胺同类物，荧光共轭物和磺酸盐，并通过计算预测了A _2A AR结合模式。最佳正丁基间隔基被并入以下A _2A AR选择性（K _i，nM）共轭物中：BODIPY630 / 650衍生物11（MRS7396，24.6）和AlexaFluor488衍生物12（MRS7416，30.3）。流式细胞仪检测hA _2A中的12表达AR的HEK-293细胞表现出饱和结合（低非特异性）和被已知的A _2A AR拮抗剂抑制。基于结合和功能测定，水溶性磺酸盐13是高效的（K _i = 6.2 nM）和选择性的A _2A AR拮抗剂。对接和分子动力学模拟预测了这些扩链配体与A _2A AR相互作用的远端区域。11个的BODIPY630 / 650荧光团埋在疏水的螺旋间（TM1 / TM7）区域中，而12个的AlexaFluor488与亲水的细胞外环相关。总之，我们已经确定了针对A的新型高亲和力拮抗剂探针_2A AR药物发现和表征。

更新日期：2017-08-16

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