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Design and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism

dc.creatorDéciga-Campos, Myrnaes_ES
dc.creatorMelo-Hernández, Luis Albertoes_ES
dc.creatorTorres-Gómez, Héctores_ES
dc.creatorWünsch, Bernhardes_ES
dc.creatorSchepmann, Dirkes_ES
dc.creatorGonzález-Trujano, María Evaes_ES
dc.creatorEspinosa-Juárez, Josuées_ES
dc.creatorLópez-Muñoz, Francisco Javieres_ES
dc.creatorNavarrete-Vázquez, Gabrieles_ES
dc.date2020
dc.date.accessioned2023-05-19T18:08:39Z
dc.date.available2023-05-19T18:08:39Z
dc.date.issued2020
dc.identifierJC02NC20es_ES
dc.identifier.issn0024-3205
dc.identifier.urihttp://repositorio.inprf.gob.mx/handle/123456789/7689
dc.identifier.urihttps://doi.org/10.1016/j.lfs.2020.117348
dc.descriptionAims: 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.es_ES
dc.formatPDFes_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.rightsAcceso Cerradoes_ES
dc.titleDesign and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonismes_ES
dc.typeArtículoes_ES
dc.contributor.affiliationSección 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.
dc.contributor.emailmdeciga@ipn.mx (M. Déciga-Campos), gabriel_navarrete@uaem.mx (G. Navarrete-Vázquez).
dc.relation.jnabreviadoLIFE SCI
dc.relation.journalLife Sciences
dc.identifier.placePaíses Bajos
dc.date.published2020
dc.identifier.organizacionInstituto Nacional de Psiquiatría Ramón de la Fuente Muñiz
dc.identifier.eissn1879-0631
dc.identifier.doi10.1016/j.lfs.2020.117348
dc.subject.kwAging
dc.subject.kwBarnes maze
dc.subject.kwMemory
dc.subject.kwOrchidectomy
dc.subject.kwTestosterone


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