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首页> 外文期刊>Journal of Medicinal Chemistry >Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology.
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Novel 1-hydroxyazole bioisosteres of glutamic acid. Synthesis, protolytic properties, and pharmacology.

机译：谷氨酸的新型1-羟基唑生物等排体。合成，蛋白水解性质和药理学。

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摘要

A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including a series of Glu receptor binding assays, uptake studies on native as well as cloned Glu uptake systems, and the electrophysiological rat cortical slice model. Compounds 7a,b, analogues of AMPA bearing a 1-hydroxy-5-pyrazolyl moiety as the distal carboxylic functionality, showed only moderate affinity for [3H]AMPA receptor binding sites (IC(50) = 2.7 +/- 0.4 microM and IC(50) = 2.6 +/- 0.6 microM, respectively), correlating with electrophysiological data from the rat cortical wedge model (EC(50) = 280 +/- 48 microM and EC(50) = 586 +/- 41 microM, respectively). 1-Hydroxy-1,2,3-triazol-5-yl analogues of AMPA, compounds 8a,b, showed high affinity for [3H]AMPA receptor binding sites (IC(50) = 0.15 +/- 0.03 microM and IC(50) = 0.13 +/- 0.02 microM, respectively). Electrophysiological data showed that compound 8a was devoid of activity in the rat cortical wedge model (EC(50) > 1000 microM), whereas the corresponding 4-methyl analogue 8b was a potent AMPA receptor agonist (EC(50) = 15 +/- 2 microM). In accordance with this disparity, compound 8a was found to inhibit synaptosomal [3H]D-aspartic acid uptake (IC(50) = 93 +/- 25 microM), as well as excitatory amino acid transporters (EAATs) EAAT1 (IC(50) = 100 +/- 30 microM) and EAAT2 (IC(50) = 300 +/- 80 microM). By contrast, compound 8b showed no appreciable affinity for Glu uptake sites, neither synaptosomal nor cloned. Compounds 9a-c and 10a,b, possessing 1-hydroxyimidazole as the terminal acidic function, were devoid of activity in all of the systems tested. Protolytic properties of compounds 7a,b, 8b, and 9b were determined by titration, and a correlation between the pK(a) values and the activity at AMPA receptors was apparent. Optimized structures of all the synthesized ligands were fitted to the known crystal structure of an AMPA-GluR2 construct. Where substantial reduction or abolition of affinity at AMPA receptors was observed, this could be rationalized on the basis of the ability of the ligand to fit the construct. The results presented in this article point to the utility of 1-hydroxypyrazole and 1,2,3-hydroxytriazole as bioisosteres of carboxylic acids at Glu receptors and transporters. None of the compounds showed significant activity at metabotropic Glu receptors.
机译：合成了多种1-羟基唑衍生物，作为（S）-谷氨酸（Glu）的生物等排体和AMPA受体激动剂（R，S）-2-氨基-3-（3-羟基-5-甲基- 4-异恶唑基）丙酸（AMPA，3b）。所有化合物均进行了体外药理研究，包括一系列Glu受体结合测定，天然和克隆Glu摄取系统的摄取研究以及电生理大鼠皮层切片模型。化合物7a，b（带有1-羟基-5-吡唑基部分作为远端羧基官能团的AMPA类似物）对[3H] AMPA受体结合位点仅显示中等亲和力（IC（50）= 2.7 +/- 0.4 microM和IC （50）= 2.6 +/- 0.6 microM），分别与大鼠皮质楔形模型的电生理数据相关（EC（50）= 280 +/- 48 microM和EC（50）= 586 +/- 41 microM ）。化合物8a，b的AMPA的1-羟基-1,2,3-三唑-5-基类似物对[3H] AMPA受体结合位点表现出高亲和力（IC（50）= 0.15 +/- 0.03 microM和IC（ 50）分别为0.13 +/- 0.02 microM）。电生理数据表明，化合物8a在大鼠皮质楔形模型中没有活性（EC（50）> 1000 microM），而相应的4-甲基类似物8​​b是有效的AMPA受体激动剂（EC（50）= 15 +/- 2 microM）。根据这种差异，发现化合物8a抑制突触体[3H] D-天冬氨酸摄取（IC（50）= 93 +/- 25 microM），以及兴奋性氨基酸转运蛋白（EAAT）EAAT1（IC（50 ）= 100 +/- 30 microM）和EAAT2（IC（50）= 300 +/- 80 microM）。相反，化合物8b对突触小体或克隆均未显示出对Glu摄取位点的明显亲和力。具有1-羟基咪唑作为末端酸性官能团的化合物9a-c和10a，b在所有测试的系统中均没有活性。通过滴定确定化合物7a，b，8b和9b的蛋白水解性质，并且pK（a）值与AMPA受体活性之间的相关性很明显。所有合成配体的优化结构都适合AMPA-GluR2构建体的已知晶体结构。在观察到对AMPA受体的亲和力显着降低或消除的情况下，这可以根据配体适合构建体的能力来合理化。本文介绍的结果指出了1-羟基吡唑和1,2,3-羟基三唑作为羧酸在Glu受体和转运蛋白上的生物等排体的用途。没有一种化合物对代谢型Glu受体表现出显着的活性。

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