Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs.
Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs.
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DOI：
10.1016/j.bmc.2010.04.044
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Sakai, Ryuichi
中科院分区：
文献类型：
--
作者：
Oikawa, Masato;Ikoma, Minoru;Sasaki, Makoto;Gill, Martin B.;Swanson, Geoffrey T.;Shimamoto, Keiko;Sakai, Ryuichi
在这里，我们报告了我们的第二代合成12个人工谷氨酸类似物，从杂三轮中间体3a-3d开始，容易在三个步骤中制备，包括串联Ugi/Diels-Alder反应。新的合成方法使用亚胺酯中间体用于吡咯烷酮的脱氧（10a-10 d至6a-6d），并且每个高级中间体6a-6d在1-2步中多样化为三个谷氨酸类似物（1a-1d，5a-5d，7a-7 d）。体外电生理学试验表明，新的哌啶型类似物7 c改变神经元功能的效力低于1a。相反，颅内注射7 c到小鼠产生了更大程度的活动减退比1a。我们最近的研究表明，这一系列的化合物拮抗AMPA型谷氨酸受体介导的电流在亚型选择性的方式。更有效地合成这套新的神经活性分子将有助于其药理学特性。
Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a–3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a–10d to 6a–6d), and each advanced intermediate 6a-–6d was diversified into three glutamate analogs (1a–1d, 5a–5d, 7a–7d) in 1–2 steps. In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization.
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影响因子：
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