6 Hz 活性抗惊厥氟化 N-苯甲酰胺烯胺酮及其抑制神经元活性。
6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity.
机构信息
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, One Backbone Road, Princess Anne, MD 21853, USA.
Department of Anatomy, College of Medicine, Howard University, 520 W Street, NW, Washington, DC 20059, USA.
出版信息
Int J Environ Res Public Health. 2018 Aug 20;15(8):1784. doi: 10.3390/ijerph15081784.
A small library of novel fluorinated N-benzamide enaminones were synthesized and evaluated in a battery of acute preclinical seizure models. Three compounds (GSA 62, TTA 35, and WWB 67) were found to have good anticonvulsant activity in the 6-Hz 'psychomotor' 44-mA rodent model. The focus of this study was to elucidate the active analogs' mode of action on seizure-related molecular targets. Electrophysiology studies were employed to evaluate the compounds' ability to inhibit neuronal activity in central olfactory neurons, mitral cells, and sensory-like ND7/23 cells, which express an assortment of voltage and ligand-gated ion channels. We did not find any significant effects of the three compounds on action potential generation in mitral cells. The treatment of ND7/23 cells with 50 µM of GSA 62, TTA 35, and WWB 67 generated a significant reduction in the amplitude of whole-cell sodium currents. Similar treatment of ND7/23 cells with these compounds had no effect on T-type calcium currents, indicating that fluorinated N-benzamide enaminone analogs may have a selective effect on voltage-gated sodium channels, but not calcium channels.
合成了一系列新型氟化 N-苯甲酰胺烯胺酮，并在一系列急性临床前癫痫模型中进行了评估。在 6-Hz“精神运动性”44-mA 啮齿动物模型中，发现三种化合物（GSA 62、TTA 35 和 WWB 67）具有良好的抗惊厥活性。本研究的重点是阐明活性类似物对与癫痫相关的分子靶点的作用模式。电生理学研究用于评估化合物抑制中枢嗅觉神经元、僧帽细胞和感觉样 ND7/23 细胞中神经元活性的能力，这些细胞表达各种电压和配体门控离子通道。我们没有发现这三种化合物对僧帽细胞动作电位产生有任何显著影响。用 50 µM 的 GSA 62、TTA 35 和 WWB 67 处理 ND7/23 细胞，会导致全细胞钠电流幅度显著降低。用这些化合物类似地处理 ND7/23 细胞对 T 型钙电流没有影响，表明氟化 N-苯甲酰胺烯胺酮类似物可能对电压门控钠通道具有选择性作用，但对钙通道没有作用。
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