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

Giuseppe Romeo,Sebastiano Intagliata,Jay P Mclaughlin,Lisa L Wilson,Loredana Salerno,Orazio Prezzavento,Maria N Modica,Valeria Pittalà,Emanuela Arena,Federica Bonanno

doi:10.1021/acschemneuro.1c00106

Giuseppe Romeo, Sebastiano Intagliata + Show 8 more

Open Access

https://doi.org/10.1021/acschemneuro.1c00106

Copy DOI

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.

Highlights

The σ-1 receptor (σ1R) was initially categorized as an opioid receptor subtype because of the binding with the nonselective benzomorphan alazocine (SKF10,047).[1]
Subsequent studies have proven that naloxone did not possess antagonism at this receptor,[2] and later molecular cloning and the X-ray crystallographic structure of the human σ1R revealed no homology with opioid receptors.[3,4]
The protein has just recently been cloned, with a sequence identical to the transmembrane protein 97 (TMEM97), a protein involved in cholesterol homeostasis.[9]

Summary

Introduction

The σ-1 receptor (σ1R) was initially categorized as an opioid receptor subtype because of the binding with the nonselective benzomorphan alazocine (SKF10,047).[1] Subsequent studies have proven that naloxone did not possess antagonism at this receptor,[2] and later molecular cloning and the X-ray crystallographic structure of the human σ1R revealed no homology with opioid receptors.[3,4] unlike opioid receptors, which possess the seven-transmembrane domain structure characteristics of G protein-coupled receptors, σ1R is a transmembrane protein that is present in numerous oligomeric states.[4] The protomer contains one transmembrane domain, five α helices, and 10 β strands forming the ligand-binding pocket.[4,5]. Like σ1R, σ2R/TMEM97 was initially miscategorized and correlated to the progesterone membrane component 1 (PGRMC1), which was thought to be the σ2R binding site.[10] further studies clarified that σ2R/TMEM97 might still interact with PGRMC1 and LDLR (low-density lipoprotein receptor), forming a ternary complex that mediates LDL internalization and trafficking.[11,12]

Methods

Results

Conclusion