A series of structurally novel heterotricyclic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-selective antagonists
A series of structurally novel heterotricyclic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-selective antagonists
复制标题
DOI：
10.1111/j.1476-5381.2010.00784.x
复制
发表时间：
2010-07-01
影响因子：
7.3
通讯作者：
Swanson, G. T.
中科院分区：
文献类型：
--
作者：
Gill, M. B.;Frausto, S.;Swanson, G. T.
背景与目的：近年来，通过引入海人酸和neodysiherbaine A的结构元素，合成了一类新的杂三环谷氨酸类似物。这些“IKM”化合物中有几种不是作为惊厥剂，而是显著抑制小鼠的中枢神经系统活动。在这里，我们的药理学特征的一系列集中在最有效的这些分子，IKM-159.Experimental方法：IKM化合物的药理活性和特异性的特点是使用全细胞膜片钳记录从神经元和异源受体表达系统，结合放射性配体binding techniques.Key结果：大多数的IKM化合物测试减少兴奋性突触传递神经元培养，和IKM-159抑制突触电流从海马切片CA 1锥体神经元。IKM-159抑制谷氨酸诱发的全细胞电流从重组GluA 2-和GluA 4-含有α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸酯（AMPA）受体最有力，而红藻氨酸和NMDA受体电流没有减少IKM-159。稳态电流的拮抗作用是激动剂浓度依赖性的，这表明其作用机制是竞争性的，虽然它矛盾地没有取代[3 H]-AMPA从受体结合位点。IKM-159减少自发动作电位发射在控制条件下培养的海马神经元和在一个在体外模型的癫痫持续状态。结论和影响：IKM-159是一种AMPA受体选择性拮抗剂。IKM-159和相关的氮杂环化合物代表了结构新颖的AMPA受体拮抗剂，具有可接近的合成途径和潜在的独特药理学，可用于探索特定受体群体在神经生理学和神经病理学过程中的作用。
Background and purpose:A new class of heterotricyclic glutamate analogues recently was generated by incorporating structural elements of two excitotoxic marine compounds, kainic acid and neodysiherbaine A. Rather than acting as convulsants, several of these 'IKM' compounds markedly depressed CNS activity in mice. Here, we characterize the pharmacological profile of the series with a focus on the most potent of these molecules, IKM-159.Experimental approach:The pharmacological activity and specificity of IKM compounds were characterized using whole-cell patch clamp recording from neurons and heterologous receptor expression systems, in combination with radioligand binding techniques.Key results:The majority of the IKM compounds tested reduced excitatory synaptic transmission in neuronal cultures, and IKM-159 inhibited synaptic currents from CA1 pyramidal neurons in hippocampal slices. IKM-159 inhibited glutamate-evoked whole-cell currents from recombinant GluA2- and GluA4-containing alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors most potently, whereas kainate and NMDA receptor currents were not reduced by IKM-159. Antagonism of steady-state currents was agonist concentration dependent, suggesting that its mechanism of action was competitive, although it paradoxically did not displace [3H]-AMPA from receptor binding sites. IKM-159 reduced spontaneous action potential firing in both cultured hippocampal neurons in control conditions and during hyperactive states in an in vitro model of status epilepticus.Conclusions and implications:IKM-159 is an AMPA receptor-selective antagonist. IKM-159 and related nitrogen heterocycles represent structurally novel AMPA receptor antagonists with accessible synthetic pathways and potentially unique pharmacology, which could be of use in exploring the role of specific populations of receptors in neurophysiological and neuropathological processes.