Department of Excellence of Biotechnology, Chemistry and Pharmacy, 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Department of Experimental Medicine Tor Vergata, University of Rome, Via Montpellier 1, 00121 Rome, Italy.
ACS Chem Neurosci. 2021 May 5;12(9):1716-1736. doi: 10.1021/acschemneuro.1c00192. Epub 2021 Apr 23.
Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor . When tested in two rodent models of epilepsy, reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (-). Biological studies highlighted and as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, and could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for (Langendorff perfused rat heart). Finally, the new analogue reduced the severity of the pilocarpine-induced status epilepticus as observed for .
颞叶癫痫是最常见的癫痫类型，目前的抗癫痫药物在许多患者中无效。内源性大麻素系统与癫痫发作的按需保护反应有关。阻断内源性大麻素的分解代谢会产生抗癫痫作用，而没有精神作用。我们在此报告了从我们的原型抑制剂进一步研究开始，发现具有有前景的抗癫痫疗效的选择性花生四烯酸酰胺水解酶（FAAH）抑制剂。当在两种癫痫啮齿动物模型中进行测试时， 减少了匹罗卡品诱导的癫痫持续状态的严重程度和海马最大齿状回激活的延长。值得注意的是， 不影响海马齿状回的长时程突触可塑性。这些数据促使我们进一步努力，旨在发现新的抗癫痫药物，开发一组新的 FAAH 抑制剂（-）。生物学研究突出了 和 作为进一步研究的最佳表现类似物。在基于细胞的研究中，使用神经母细胞瘤细胞系， 和 可以通过降低 NF-kB p65 的 DNA 结合活性来减轻氧化炎症状态，而没有细胞毒性作用。 （Langendorff 灌注大鼠心脏）排除了对心脏的不良影响。最后，新类似物 减少了匹罗卡品诱导的癫痫持续状态的严重程度，如 所观察到的那样。
