AIMS Haloperidol is a neuroleptic drug with high affinity towards the σ1 receptor (σ1R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N‑(1‑benzylpiperidin‑4-yl)‑4‑fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain). MAIN METHODS LMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic (1H and 13C NMR) and spectrometric mass (electronic impact) techniques. Additionally, in silico predictions of pharmacokinetic, pharmacodynamic and toxicological properties were obtained, with promising results. A competitive binding assay using radioligands was employed to evaluate the in vitro affinity for σ1R, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI. KEY FINDINGS LMH-2 showed high affinity for σ1R in an in vitro binding assay, with a Ki = 6.0 nM and a high σ1R/σ2R selectivity ratio. Molecular docking studies were carried out to determine the binding energy and to analyze LMH-2-protein interactions. Through an in silico pharmacological consensus analysis, LMH-2 was considered safe for in vivo evaluation. Thus, LMH-2 had dose-dependent antiallodynic and antihyperalgesic activities; its efficacy was comparable to that of gabapentin, but its potency was 2-times higher than this drug. SIGNIFICANCE LMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σ1R, suggesting its potential use as an analgesic drug for neuropathic pain.

中文翻译：

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N-(苄基哌啶基)-4-氟苯甲酰胺的设计和合成：一种氟哌啶醇类似物，通过 σ1 受体拮抗作用减少神经性伤害感受。


目的 氟哌啶醇是一种对 σ1 受体 (σ1R) 具有高亲和力的精神安定药，可作为拮抗剂减少神经性疼痛，但具有中枢神经系统副作用。这项工作描述了新型类似物 N-(1-苄基哌啶-4-基)-4-氟苯甲酰胺 (LMH-2) 的设计和合成，该类似物对坐骨神经慢性收缩性损伤引起的神经病大鼠产生抗痛觉过敏和抗异常疼痛作用神经（CCI），比加巴喷丁（治疗神经性疼痛最广泛使用的药物）更活跃。主要方法LMH-2被设计为氟哌啶醇类似物。其结构通过光谱（1H 和 13C NMR）和光谱质量（电子轰击）技术进行了表征。此外，还获得了药代动力学、药效学和毒理学特性的计算机预测，并取得了有希望的结果。采用放射性配体的竞争性结合测定来评估 σ1R 的体外亲和力，而使用具有 CCI 的 Wistar 大鼠研究体内抗痛觉过敏和抗异常疼痛活性。主要发现 LMH-2 在体外结合测定中显示出对 σ1R 的高亲和力，Ki = 6.0 nM 和高 σ1R/σ2R 选择性比。进行分子对接研究以确定结合能并分析LMH-2-蛋白质相互作用。通过计算机药理学共识分析，LMH-2 被认为可安全用于体内评估。因此，LMH-2 具有剂量依赖性的抗异常疼痛和抗痛觉过敏活性；其功效与加巴喷丁相当，但效力比该药高2倍。意义 LMH-2 给药通过 σ1R 的拮抗作用产生抗痛觉过敏和抗异常疼痛作用，表明其作为神经性疼痛的镇痛药物的潜在用途。