Hybrid Ortho/Allosteric Ligands for the Adenosine A1 Receptor
Hybrid Ortho/Allosteric Ligands for the Adenosine A1 Receptor
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DOI：
10.1021/jm901252a
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发表时间：
2010-04-22
影响因子：
7.3
通讯作者：
IJzerman, Adriaan P.
中科院分区：
文献类型：
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作者：
Narlawar, Rajeshwar;Lane, J. Robert;IJzerman, Adriaan P.
许多G蛋白偶联受体（GPCR），包括腺苷A（1）受体（A（1）AR），已被证明是由小分子配体变构调节。到目前为止，在缺乏结构信息的情况下，A（1）AR上变构位点的确切位置尚不清楚。我们合成了一系列二价配体（4），其在正构和变构药效团之间具有增加的接头长度，并使用这些作为工具来搜索A（1）AR上的变构位点。在不存在和存在参比变构增强剂（2-氨基-4，5-二甲基-3-噻吩基）-[3-（三氟甲基）苯基]甲酮，PD 81，723（1）的情况下，在平衡放射性配体置换和功能测定中检测化合物。具有9个碳原子间隔基的二价配体N-6-[2-氨基-3-（3，4-二氯苯甲酰基）-4，5，6，7-四氢噻吩并[2，3-c]-吡啶-6-基-9-壬氧基-4-苯基]-腺苷4 h（LUF 6258）在1存在下未显示亲和力或效力的显著变化，表明该配体桥接受体上的两个位点。此外，与母体单价激动剂2相比，4 h显示效力增加，但效力没有增加。从分子模拟研究中，我们推测A（1）AR的变构位点位于正构位点附近，可能在受体的第二个细胞外环的边界内。
Many G protein-coupled receptors (GPCRs), including the adenosine A(1) receptor (A(1)AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of the allosteric site on the A(1)AR is not known. We synthesized a series of bivalent ligands (4) with an increasing linker length between the orthosteric and allosteric pharmacophores and used these as tools to search for the allosteric site on the A(1)AR. The compounds were tested in both equilibrium radioligand displacement and functional assays in the absence and presence of a reference allosteric enhancer, (2-amino-4,5-dimethy1-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone, PD81,723 (1). Bivalent ligand N-6-[2-amino-3-(3,4-dichlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]-pyridin-6-yl-9-nonyloxy-4-phenyl]-adenosine 4h (LUF6258) with a 9 carbon atom spacer did not show significant changes in affinity or potency in the presence of 1, indicating that this ligand bridged both sites on the receptor. Furthermore, 4h displayed an increase in efficacy, but not potency, compared to the parent, monovalent agonist 2. From molecular modeling studies, we speculate that the allosteric site of the A(1)AR is located in the proximity of the orthosteric site, possibly within the boundaries of the second extracellular loop of the receptor.