Papers of the Week

σ-1 receptors (σR) 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 σR and selectivity over the σ-2 receptor (σR). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one () showed the highest σR receptor affinity ( σ = 1.6 nM) among the series with a significant improvement of the σR selectivity ( σ/ σ 886) compared to the lead compound ( σ/ σ 432). Compound 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 demonstrated no significant effects in a rotarod assay, suggesting that this σR antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σR antagonists as potential therapeutics for chronic pain.