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

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 K_i = 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.