Farinato Alessandro, Cavalluzzi Maria Maddalena, Altamura Concetta, Campanale Carmen, Laghetti Paola, Saltarella Ilaria, Delre Pietro, Barbault Arthur, Tarantino Nancy, Milani Gualtiero, Rotondo Natalie Paola, Di Cesare Mannelli Lorenzo, Ghelardini Carla, Pierno Sabata, Mangiatordi Giuseppe Felice, Lentini Giovanni, Desaphy Jean-François
Section of Pharmacology, Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.
Section of Medicinal Chemistry, Department of Pharmacy - Drug Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.
ACS Med Chem Lett. 2023 Jun 23;14(7):999-1008. doi: 10.1021/acsmedchemlett.3c00224. eCollection 2023 Jul 13.
Several commercially available and newly synthesized riluzole analogs were evaluated in vitro as voltage-gated skeletal muscle sodium-channel blockers. Data obtained from the patch-clamp technique demonstrated that potency is well correlated with lipophilicity and the introduction of a protonatable amino function in the benzothiazole 2-position enhances the use-dependent behavior. The most interesting compound, the 2-piperazine analog of riluzole (), although slightly less potent than the parent compound in the patch-clamp assay as well as in an in vitro model of myotonia, showed greater use-dependent Nav1.4 blocking activity. Docking studies allowed the identification of the key interactions that makes with the amino acids of the local anesthetic binding site within the pore of the channel. The reported results pave the way for the identification of novel compounds useful in the treatment of cell excitability disorders.
对几种市售的和新合成的利鲁唑类似物进行了体外评估，以确定它们作为电压门控性骨骼肌钠通道阻滞剂的效果。从膜片钳技术获得的数据表明，效力与亲脂性密切相关，并且在苯并噻唑的2位引入可质子化的氨基官能团可增强使用依赖性行为。最有趣的化合物，即利鲁唑的2-哌嗪类似物（），尽管在膜片钳试验以及肌强直体外模型中比母体化合物的效力略低，但显示出更强的使用依赖性Nav1.4阻断活性。对接研究确定了与通道孔内局部麻醉药结合位点的氨基酸形成的关键相互作用。所报道的结果为鉴定可用于治疗细胞兴奋性疾病的新型化合物铺平了道路。
