Novel analogs and stereoisomers of the marine toxin neodysiherbaine with specificity for kainate receptors
Novel analogs and stereoisomers of the marine toxin neodysiherbaine with specificity for kainate receptors
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DOI：
10.1124/jpet.107.129890
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发表时间：
2008-02-01
影响因子：
3.5
通讯作者：
Swanson, Geoffrey T.
中科院分区：
文献类型：
--
作者：
Lash, L. Leanne;Sanders, James M.;Swanson, Geoffrey T.
红藻氨酸受体（KAR）（谷氨酸门控离子通道家族）的拮抗剂在许多神经病理学的动物模型中有效，包括癫痫、偏头痛和焦虑。为了产生具有新的选择性的红藻氨酸受体的分子，我们产生了三组类似物相关的天然海洋惊厥neodysiherbaine（neoDH），我们的特点是他们的药理学概况。用重组α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和KAR进行的放射性配体置换试验表明，neoDH分子上两个位置的官能团是关键的药理学决定因素;仅与谷氨酸受体（GluR）5-2a亚基结合对关键官能团的结构修饰相对不敏感。其中L-谷氨酸同源物通过差向异构化被破坏的NeoDH类似物保留了对GluR 5 -2a和GluR 6a KAR亚基的低亲和力。大多数类似物在表达GluR 5 -2a KAR的人胚肾-T/17细胞的电生理记录中显示激动剂活性，类似于天然惊厥剂neoDH。相反，2，4-epi-neoDH抑制GluR 5 -2a和GluR 6a受体表达细胞诱发的谷氨酸电流。因此，该化合物代表了第一种对GluR 5 -2a和GluR 6a KAR亚基表现出功能性拮抗剂活性而对AMPA受体亚基没有同时活性的化合物。最后，GluR 5 -2a亚基的合成配体的结合亲和力与它们的致神经毒性效能密切相关，强烈支持含有该亚基的受体在对KAR激动剂的惊厥反应中的作用。这里描述的类似物提供了进一步了解KARs的配体选择性的结构决定因素，并可能代表有用的药理学工具，用于研究KARs在突触生理学和病理学中的作用。
Antagonists for kainate receptors (KARs), a family of glutamate-gated ion channels, are efficacious in a number of animal models of neuropathologies, including epilepsy, migraine pain, and anxiety. To produce molecules with novel selectivities for kainate receptors, we generated three sets of analogs related to the natural marine convulsant neodysiherbaine (neoDH), and we characterized their pharmacological profiles. Radioligand displacement assays with recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KARs demonstrated that functional groups at two positions on the neoDH molecule are critical pharmacological determinants; only binding to the glutamate receptor (GluR)5-2a subunit was relatively insensitive to structural modifications of the critical functional groups. NeoDH analogs in which the L-glutamate congener was disrupted by epimerization retained low affinity for GluR5-2a and GluR6a KAR subunits. Most of the analogs showed agonist activity in electrophysiological recordings from human embryonic kidney-T/17 cells expressing GluR5-2a KARs, similar to the natural convulsant neoDH. In contrast, 2,4-epi-neoDH inhibited glutamate currents evoked from both GluR5-2a and GluR6a receptor-expressing cells. Therefore, this compound represents the first compound to exhibit functional antagonist activity on GluR5-2a and GluR6a KAR subunits without concurrent activity on AMPA receptor subunits. Finally, binding affinity of the synthetic ligands for the GluR5-2a subunit closely correlated with their seizurogenic potency, strongly supporting a role for receptors containing this subunit in the convulsant reaction to KAR agonists. The analogs described here offer further insight into structural determinants of ligand selectivity for KARs and potentially represent useful pharmacological tools for studying the role of KARs in synaptic physiology and pathology.