Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: Interactions with cyclothiazide and GYKI 52466
Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: Interactions with cyclothiazide and GYKI 52466
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DOI：
10.1124/mol.58.4.802
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发表时间：
2000-10-01
影响因子：
3.6
通讯作者：
Lynch, G
中科院分区：
文献类型：
--
作者：
Arai, AC;Kessler, M;Lynch, G
苯甲酰胺型的R，S-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体上调剂（“ampakines”）先前已显示在体内和体外增强兴奋性突触传递以及在切除的贴片中增强AMPA受体电流。本研究分析了属于苯并恶嗪亚组的安巴金（CX 614; 2 H，3 H，6aH-吡咯烷[2”，1”-3 '，2'] 1，3-恶嗪并[6 '，5'-5，4]苯并[e] 1，4-二氧杂环己烷-10-酮）的作用，其特征在于更大的结构刚性和更高的效力。CX 614增强了海马脑片的场兴奋性突触后电位的大小（幅度和持续时间），并在神经元培养物中自发诱发兴奋性突触后电流，EC 50值为20至40 μ M。该化合物阻断脱敏（EC 50 = 44 μ M）和减缓失活的响应谷氨酸的一个因素的8.4在切除的补丁。通过同源重组AMPA受体的电流增强，EC 50值在GluR 1 -3翻转亚基（19-37 μ M）之间没有很大差异，但在相应的翻转变体上显示出略低的效力。使用[H-3]fluorowillardiine结合的调制的竞争实验表明，CX 614和环噻嗪共享一个共同的结合位点，但环噻嗪似乎结合到一个额外的网站不承认的ampakine。CX 614没有逆转GYKI 52466对短暂谷氨酸脉冲的反应，这表明它们通过不同的位点起作用，这一结论在结合实验中得到了证实。总之，这些结果扩展了先前的证据，即ampakines在增强突触反应中是有效的，最有可能是通过减缓失活，并且它们的作用是通过仅与其他调节剂部分共享的位点发挥的。
R,S-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor up-modulators of the benzamide type ("ampakines") have previously been shown to enhance excitatory synaptic transmission in vivo and in vitro and AMPA receptor currents in excised patches. The present study analyzed the effects of an ampakine (CX614; 2H, 3H, 6aH-pyrrolidino[2", 1"-3', 2']1,3-oxazino[6',5'-5,4]benzo[e]1,4-dioxan-10-one) that belongs to a benzoxazine subgroup characterized by greater structural rigidity and higher potency. CX614 enhanced the size (amplitude and duration) of field excitatory postsynaptic potentials in hippocampal slices and autaptically evoked excitatory postsynaptic currents in neuronal cultures with EC50 values of 20 to 40 mu M. The compound blocked desensitization (EC50 = 44 mu M) and slowed deactivation of responses to glutamate by a factor of 8.4 in excised patches. Currents through homomeric, recombinant AMPA receptors were enhanced with EC50 values that did not differ greatly across GluR1-3 flop subunits (19-37 mu M) but revealed slightly lower potency at corresponding flip variants. Competition experiments using modulation of [H-3]fluorowillardiine binding suggested that CX614 and cyclothiazide share a common binding site but cyclothiazide seems to bind to an additional site not recognized by the ampakine. CX614 did not reverse the effect of GYKI 52466 on responses to brief glutamate pulses, which indicates that they act through separate sites, a conclusion that was confirmed in binding experiments. In sum, these results extend prior evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation, and that their effects are exerted through sites that are only in part shared with other modulators.