Gill M B, Frausto S, Ikoma M, Sasaki M, Oikawa M, Sakai R, Swanson G T
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Br J Pharmacol. 2010 Jul;160(6):1417-29. doi: 10.1111/j.1476-5381.2010.00784.x.
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.
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.
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 [(3)H]-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.
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.
最近通过结合两种兴奋性毒性海洋化合物——海藻酸和新海蟾蜍毒素A的结构元素，生成了一类新型的杂三环谷氨酸类似物。这些“IKM”化合物中的几种并未表现出惊厥作用，反而显著降低了小鼠的中枢神经系统活性。在此，我们以该系列中最有效的分子IKM - 159为重点，对其药理学特性进行表征。
使用神经元的全细胞膜片钳记录和异源受体表达系统，并结合放射性配体结合技术，对IKM化合物的药理活性和特异性进行表征。
测试的大多数IKM化合物降低了神经元培养物中的兴奋性突触传递，IKM - 159抑制了海马切片中CA1锥体神经元的突触电流。IKM - 159最有效地抑制了含重组GluA2和GluA4的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的谷氨酸诱发的全细胞电流，而IKM - 159并未降低海人藻酸和NMDA受体电流。稳态电流的拮抗作用呈激动剂浓度依赖性，表明其作用机制是竞争性的，尽管自相矛盾的是它并未从受体结合位点上取代[³H]-AMPA。IKM - 159在对照条件下以及癫痫持续状态体外模型的多动状态期间，均降低了培养的海马神经元中的自发动作电位发放。
IKM - 159是一种AMPA受体选择性拮抗剂。IKM - 159及相关的氮杂环代表了结构新颖的AMPA受体拮抗剂，具有可行的合成途径和潜在独特的药理学特性，可用于探索特定受体群体在神经生理和神经病理过程中的作用。
