Open AccessDevelopment of New Benzylpiperazine Derivatives as σ1 Receptor Ligands with in Vivo Antinociceptive and Anti-Allodynic Effects
Author(s) -
Giuseppe Romeo,
Federica Bonanno,
Lisa Wilson,
Elena Arena,
Maria Modica,
Valeria Pittalà,
Loredana Salerno,
Orazio Prezzavento,
Jay P. McLaughlin,
Sebastiano Intagliata
Publication year - 2021
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.1c00106
Subject(s) - pharmacology , nociception , in vivo , chemistry , nociceptin receptor , receptor , medicine , biology , opioid , biochemistry , microbiology and biotechnology , opioid peptide
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.