Development of New Benzylpiperazine Derivatives as σ(1) Receptor Ligands with in Vivo Antinociceptive and Anti-Allodynic Effects

[Image: see text] σ-1 receptors (σ(1)R) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σ(1)R and selectivity over the σ-2 receptor (σ(2)R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ(1)R receptor affinity (K(i) σ(1) = 1.6 nM) among the series with a significant improvement of the σ(1)R selectivity (K(i) σ(2)/K(i) σ(1)= 886) compared to the lead compound 8 (K(i) σ(2)/K(i) σ(1)= 432). Compound 15 was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3–60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound 15 demonstrated no significant effects in a rotarod assay, suggesting that this σ(1)R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ(1)R antagonists as potential therapeutics for chronic pain.