Development of New Benzylpiperazine Derivatives as σ₁ Receptor Ligands with in Vivo Antinociceptive and Anti-Allodynic Effects.

ABSTRACT: σ-1 receptors (σ₁R) 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 σ₁R and selectivity over the σ-2 receptor (σ₂R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ₁R receptor affinity (K_i σ₁ = 1.6 nM) among the series with a significant improvement of the σ₁R selectivity (K_i σ₂/K_i σ₁ = 886) compared to the lead compound 8 (K_i σ₂/K_i σ₁ = 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 σ₁R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ₁R antagonists as potential therapeutics for chronic pain.

SUBMITTER: Romeo G 

PROVIDER: S-EPMC8291485 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature