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 (Ki σ1 = 1.6 nM) among the series with a significant improvement of the σ1R selectivity (Ki σ2/Ki σ1= 886) compared to the lead compound 8 (Ki σ2/Ki 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.

• Authors: Giuseppe Romeo, Federica Bonanno, Lisa L Wilson, Emanuela Arena, Maria N Modica, Valeria Pittalà, Loredana Salerno, Orazio Prezzavento, Jay P McLaughlin, Sebastiano Intagliata
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 12 Issue 11 Pg. 2003-2012 (06 02 2021) ISSN: 1948-7193 [Electronic] United States
• PMID: 34019387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Ligands
• Receptors, sigma
• sigma-1 receptor

Topics

• Analgesics (pharmacology)
• Animals
• Hyperalgesia (drug therapy)
• Ligands
• Mice
• Receptors, sigma
• Structure-Activity Relationship