Adenosine A2A Receptor-Antagonist/Dopamine D2 Receptor-Agonist Bivalent Ligands as Pharmacological Tools to Detect A2A-D2 Receptor Heteromers
Adenosine A2A Receptor-Antagonist/Dopamine D2 Receptor-Agonist Bivalent Ligands as Pharmacological Tools to Detect A2A-D2 Receptor Heteromers
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DOI：
10.1021/jm900298c
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发表时间：
2009-09-24
影响因子：
7.3
通讯作者：
Royo, Miriam
中科院分区：
文献类型：
--
作者：
Soriano, Aroa;Ventura, Ruben;Royo, Miriam
腺苷A（2A）（A（2A）R）和多巴胺D-2（D2 R）受体介导纹状体苍白球GABA能神经元中腺苷能和多巴胺能传递之间的拮抗作用，并且是治疗帕金森病的药理学靶点。本文设计并合成了一个含有D，R激动剂和A2 AR拮抗剂的异二价配体家族，以研究A（2A）R-D2 R异聚体。具有较短接头的二价配体与D2 R或A（2A）R结合，其亲和力高于脑纹状体和共表达两种受体的细胞膜中相应单价对照。相比之下，在使用来自仅表达一种受体的细胞的膜的实验中检测到二价配体与单价配体的亲和力没有差异。这些发现表明存在A（2A）R-D2 R异聚体和异二价配体与两种受体的同时相互作用。同时相互作用产生的协同效应表明，在共转染细胞和脑纹状体中存在A（2A）R-D2 R异聚体。多巴胺/腺苷二价作用可能构成帕金森病药物治疗的新概念。
Adenosine A(2A) (A(2A)R) and dopamine D-2 (D2R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease. Here, a family of heterobivalent ligands containing a D,R agonist and an A2AR antagonist linked through a spacer of variable size was designed and synthesized to study A(2A)R-D2R heteromers. Bivalent ligands with shorter linkers bound to D2R or A(2A)R with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A(2A)R-D2R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A(2A)R-D2R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.