Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand.
Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand.
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DOI：
10.1021/bc5003373
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发表时间：
2014-10-15
影响因子：
4.7
通讯作者：
Ciruela, Francisco
中科院分区：
文献类型：
--
作者：
Isabel Bahamonde, Maria;Taura, Jaume;Paoletta, Silvia;Gakh, Andrei A.;Chakraborty, Saibal;Hernando, Jordi;Fernandez-Duenas, Victor;Jacobson, Kenneth A.;Gorostiza, Pau;Ciruela, Francisco
腺苷能系统通过G蛋白偶联的腺苷受体起作用，其已成为广泛病理状况的有希望的治疗靶点。然而，腺苷受体的普遍存在和腺苷类药物选择性的最终缺乏常常降低了它们的治疗潜力。因此，在此，我们的目标是开发新一代光可切换腺苷受体配体，其在照射时改变其内在活性，从而允许受体功能的时空控制（即，受体激活/失活依赖于位置和时机）。因此，我们合成了一个orthosteric的，光异构化，和非选择性的腺苷受体激动剂，核苷衍生物MRS 5543含有芳基重氮连接的N6取代基，在黑暗中（松弛异构体）表现为一个完整的腺苷A3受体（A3 R）和部分腺苷A2 A受体（A2 AR）激动剂。相反，在蓝光（460 nm）光异构化后，它仍然是一个完整的A3 R激动剂，但成为A2 AR拮抗剂。有趣的是，分子模拟表明，每个受体的第三胞外环内遇到的结构差异可以调节内在的受体亚型依赖性活性。总体而言，具有光开关活性的腺苷受体配体的开发扩展了支持研究的药理学工具箱，并可能开辟新的药理学机会。
The adenosinergic system operates through G protein-coupled adenosine receptors, which have become promising therapeutic targets for a wide range of pathological conditions. However, the ubiquity of adenosine receptors and the eventual lack of selectivity of adenosine-based drugs have frequently diminished their therapeutic potential. Accordingly, here we aimed to develop a new generation of light-switchable adenosine receptor ligands that change their intrinsic activity upon irradiation, thus allowing the spatiotemporal control of receptor functioning (i.e., receptor activation/inactivation dependent on location and timing). Therefore, we synthesized an orthosteric, photoisomerizable, and nonselective adenosine receptor agonist, nucleoside derivative MRS5543 containing an aryl diazo linkage on the N6 substituent, which in the dark (relaxed isomer) behaved as a full adenosine A3 receptor (A3R) and partial adenosine A2A receptor (A2AR) agonist. Conversely, upon photoisomerization with blue light (460 nm), it remained a full A3R agonist but became an A2AR antagonist. Interestingly, molecular modeling suggested that structural differences encountered within the third extracellular loop of each receptor could modulate the intrinsic, receptor subtype-dependent, activity. Overall, the development of adenosine receptor ligands with photoswitchable activity expands the pharmacological toolbox in support of research and possibly opens new pharmacotherapeutic opportunities.
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DOI：
10.1073/pnas.68.8.1820
发表时间：
1971-01-01
影响因子：
11.1
作者：
BARTELS, E;WASSERMANN, NH;ERLANGER, BF
通讯作者：
ERLANGER, BF
影响因子：
25
作者：
Banghart, M;Borges, K;Kramer, RH
通讯作者：
Kramer, RH
影响因子：
7.3
作者：
Alexander, SPH;Cooper, J;Hill, SJ
通讯作者：
Hill, SJ
DOI：
10.1126/science.1166022
发表时间：
2008-10-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gorostiza P;Isacoff EY
通讯作者：
Isacoff EY
DOI：
10.1007/978-94-007-7423-0_1
发表时间：
2014-01-01
期刊：
G PROTEIN-COUPLED RECEPTORS - MODELING AND SIMULATION
影响因子：
--
作者：
Costanzi, Stefano;Wang, Keyun
通讯作者：
Wang, Keyun