Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomás, 11340 Ciudad de México, Mexico.
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Chamilpa, Cuernavaca, Morelos 62209, Mexico.
Life Sci. 2020 Mar 15;245:117348. doi: 10.1016/j.lfs.2020.117348. Epub 2020 Jan 23.
Haloperidol is a neuroleptic drug with high affinity towards the σ receptor (σR), 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).
LMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic (H and C 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 σR, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI.
LMH-2 showed high affinity for σR in an in vitro binding assay, with a K = 6.0 nM and a high σR/σR 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.
LMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σR, suggesting its potential use as an analgesic drug for neuropathic pain.
氟哌啶醇是一种具有高亲和力的 σ 受体（σR）的神经安定药，作为拮抗剂，可减轻神经性疼痛，但具有中枢神经系统副作用。本工作描述了一种新型类似物 N-（1-苄基哌啶-4-基）-4-氟苯甲酰胺（LMH-2）的设计和合成，它在慢性坐骨神经缩窄损伤（CCI）诱导的神经病变大鼠中产生抗痛觉过敏和抗触诱发痛作用，比加巴喷丁（最广泛用于治疗神经性疼痛的药物）更有效。
LMH-2 被设计为氟哌啶醇类似物。其结构通过光谱（H 和 C NMR）和光谱质量（电子冲击）技术进行了表征。此外，还获得了药代动力学、药效学和毒理学性质的计算预测，结果有希望。使用放射性配体进行竞争性结合测定来评估其对 σR 的体外亲和力，而使用 Wistar 大鼠进行 CCI 来研究体内抗痛觉过敏和抗触诱发痛作用。
LMH-2 在体外结合测定中对 σR 具有高亲和力，K i = 6.0 nM，具有高 σR/σR 选择性比。进行了分子对接研究以确定结合能并分析 LMH-2-蛋白相互作用。通过计算药理学共识分析，认为 LMH-2 适合体内评价。因此，LMH-2 具有剂量依赖性的抗触诱发痛和抗痛觉过敏作用；其疗效与加巴喷丁相当，但效力是该药物的 2 倍。
LMH-2 通过拮抗 σR 产生抗痛觉过敏和抗触诱发痛作用，表明其可能作为治疗神经性疼痛的镇痛药。
