Design and synthesis of N­(benzylpiperidinyl)­4­fluorobenzamide: 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(1­benzylpiperidin­4-yl)­4­fluorobenzamide (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.

N-(2-morpholin-4-yl-ethyl)-2-(1naphthyloxy)acetamide inhibits the chronic constriction injury-generated hyperalgesia via the antagonism of sigma-1 receptors.

The most used therapeutic treatment to relieve neuropathic pain is that of neuromodulators such as anti-epileptics or anti-depressants; however, there are alternatives that may be potentially useful. The sigma-1 receptor is a therapeutic target that has shown favorable results at preclinical levels. The aim of this study was to evaluate the anti-hyperalgesic effect of N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy) acetamide (NMIN) in a chronic constriction injury model (CCI) and compare it both a sigma-1 antagonist (BD-1063) and also Gabapentin, as well as determine its possible role as an antagonist of sigma-1 receptors. The anti-hyperalgesic effects of Gabapentin (10.0, 17.8, 31.6, 56.2 and 100mg/kg, s.c.), BD-1063 (5.6, 10.0, 17.8, 31.6 and 56.2mg/kg, s.c.) and NMIN (31.6, 10.0, 316mg/kg and 562mg/kg, s.c.) were determined after single-doses, using the von Frey test in the CCI model. NMIN had the same efficacy as BD-1063, but both show less efficacy than Gabapentin. In an analysis of pharmacological potency, the ED50 were compared with it being found that BD-1063 is the most potent drug, followed by Gabapentin and NMIN. The anti-hyperalgesic effect of NMIN on CCI rats was reversed by (+)-pentazocine (s.c. route) and by PRE-084 (i.t. route), both sigma-1 agonists. Furthermore, NMIN reversed the hyperalgesic effect of PRE-084 in naïve rats. These results suggest that NMIN has an anti-hyperalgesic effect on the CCI model, and that one of its mechanisms of action is as a sigma-1 antagonist, being a significant role the blocking of these receptors at the spinal level.

Antinociceptive effects of a new sigma-1 receptor antagonist (N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamide) in two types of nociception.

Pain has become an active clinical challenge due its etiological heterogeneity, symptoms and mechanisms of action. In the search for new pharmacological therapeutic alternatives, sigma receptors have been proposed as drug targets. This family consists of sigma-1 and sigma-2 receptors. The sigma-1 system is involved in nociception through its chaperone activity. Additionally, it has been shown that agonist to these receptors promote related sensitisation and pain hypersensitisation, suggesting the possible use of antagonists for sigma-1 receptors as an alternative therapy. The aim of this study was to evaluate the antinociceptive effect of a new sigma-1 receptor antagonist N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamida (NMIN) in two types of pain (arthritic and neuropathic) and to compare its efficacy and potency with reference drugs. The antinociceptive effects of NMIN were quantitatively evaluated using the pain-induced functional impairment model in the rat and the acetone test in a rat model of neuropathic pain. NMIN (sigma-1 receptor affinity of 324nM) did not show any antinociceptive activity in the arthritic pain model but showed a dose-dependent anti-allodynic effect in neuropathic pain. NMIN showed a similar efficacy compared to the effects obtained with morphine and the sigma-1 antagonist BD-1063. However, these reference drugs showed increased potency compared with NMIN. Our results suggest that sigma-1 receptors may play an important direct role in neuropathic pain but not in arthritic pain, supporting the hypothesis that NMIN may be useful for the treatment of neuropathic pain.