TY - JOUR
T1 - Design and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide
T2 - A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism
AU - Déciga-Campos, Myrna
AU - Melo-Hernández, Luis Alberto
AU - Torres-Gómez, Héctor
AU - Wünsch, Bernhard
AU - Schepmann, Dirk
AU - González-Trujano, María Eva
AU - Espinosa-Juárez, Josué
AU - López-Muñoz, Francisco Javier
AU - Navarrete-Vázquez, Gabriel
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - 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.
AB - 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.
KW - Allodynia
KW - Haloperidol
KW - Hyperalgesia
KW - Neuropathic pain
KW - N‑(1‑Benzylpiperidin‑4‑yl)‑4‑fluorobenzamide
KW - σ receptor
UR - http://www.scopus.com/inward/record.url?scp=85078655966&partnerID=8YFLogxK
U2 - 10.1016/j.lfs.2020.117348
DO - 10.1016/j.lfs.2020.117348
M3 - Artículo
C2 - 31981633
AN - SCOPUS:85078655966
SN - 0024-3205
VL - 245
JO - Life Sciences
JF - Life Sciences
M1 - 117348
ER -