Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Turkey.
Drug Dev Res. 2022 Feb;83(1):184-193. doi: 10.1002/ddr.21858. Epub 2021 Jul 22.
Nafimidone is known for its clinical antiepileptic effects and alcohol derivatives of nafimidone were reported be potent anticonvulsants. These compounds are structurally similar to miconazole, which is known to inhibit cholinesterases, protect neurons, and ameliorate cognitive decline. Herein, we aimed to reveal the potential of three nafimidone alcohol esters (5 g, 5i, and 5 k), which were previously reported for their anticonvulsant effects, against co-morbidities of epilepsy such as inflammatory and neuropathic pain, cognitive and behavioral deficits, and neuron death, and understand their roles in related pathways such as γ-butyric acid type A (GABA ) receptor and cholinesterases using in vitro, in vivo and in silico methods. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used for cytotoxicity evaluation, hippocampal slice culture assay for neuroprotection, formalin test for acute and inflammatory pain, sciatic ligation for neuropathic pain, Morris water maze and open field locomotor tasks for cognitive and behavioral deficits, radioligand binding for GABA receptor affinity, spectrophotometric methods for cholinesterase inhibition in vitro, and molecular docking in silico. The compounds were non-toxic to fibroblast cells. 5 k was neuroprotective against kainic acid-induced neuron death. 5i reduced pain response of mice in both the acute and the inflammatory phases. 5i improved survival upon status epilepticus. The compounds showed no affinity to GABA receptor but inhibited acetylcholinesterase, 5 k also inhibited butyrylcholinesterase. The compounds were predicted to interact mainly with the peripheric anionic site of cholinesterase enzymes. The title compounds showed neuroprotective, analgesic, and cholinesterase inhibitory effects, thus they bear promise against certain co-morbidities of epilepsy with neurological insults.
那非米酮以其临床抗癫痫作用而闻名，其酒精衍生物被报道具有很强的抗惊厥作用。这些化合物在结构上与咪康唑相似，咪康唑已知能抑制胆碱酯酶、保护神经元并改善认知能力下降。在此，我们旨在揭示三种那非米酮醇酯（5g、5i 和 5k）的潜力，这些化合物以前曾报道过其抗惊厥作用，可对抗癫痫的共病，如炎症和神经病理性疼痛、认知和行为缺陷以及神经元死亡，并了解它们在相关途径中的作用，如γ-氨基丁酸 A 型（GABA）受体和胆碱酯酶，使用体外、体内和计算方法。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）试验用于细胞毒性评估，海马切片培养试验用于神经保护，福氏完全佐剂用于急性和炎症性疼痛，坐骨神经结扎用于神经病理性疼痛，莫里斯水迷宫和旷场运动任务用于认知和行为缺陷，放射性配体结合用于 GABA 受体亲和力，分光光度法用于体外胆碱酯酶抑制，以及计算分子对接。这些化合物对成纤维细胞无毒。5k 对红藻氨酸诱导的神经元死亡具有神经保护作用。5i 减轻了小鼠在急性和炎症期的疼痛反应。5i 改善了癫痫持续状态下的存活率。这些化合物对 GABA 受体没有亲和力，但抑制乙酰胆碱酯酶，5k 还抑制丁酰胆碱酯酶。这些化合物被预测主要与胆碱酯酶酶的外周阴离子结合位点相互作用。标题化合物显示出神经保护、镇痛和胆碱酯酶抑制作用，因此它们有望对抗具有神经损伤的癫痫的某些共病。
