Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

Abstract

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42–28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

“…This makes WLB-73502 a promising alternative for treating chronic refractory pain, potentially neuropathic cancer pain, where regular stand-alone opioids do not achieve satisfactory outcomes and are limited by drug tolerance and adverse effects 110 . In agreement with findings with WLB-73502, other bifunctional S1R antagonist/MOR agonist derivatives including piperidinamides 102 , benzylpiperazines 111 and 4-aryl-1-oxa-4,9-diazaspiro[5.5]undecanes 112 also produced fewer opioid-like side effects, thus highlighting dual S1R antagonism/MOR agonism as a hopeful avenue for the development of potent and safer analgesics 113 .…”

Bispecific Sigma1R-Antagonist/MOR-Agonist Compounds for Pain

“…Wilson et al report the results of preclinical testing of the benzylpiperazine derivative compound SI-1/28 (1-(4-{(4-hydroxymethyl)phenyl)methyl}piperazin-1-yl)-5-phenylpentan-1-one oxalate) [ 6 ]. It has about 400-fold selective affinity for S1R over S2R ( K i = 6.1 nM vs 2,583 nM, respectively); affinity for off-target sites was not reported.…”

Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain

“…As further evidence, NP is attenuated in S1R knockout (KO) mice [ 28 ]. S1R antagonists have been shown to exert antinociceptive effects in preclinical models of the inflammatory pain, ischemic pain, and neuropathic pain induced by nerve trauma or chemical injury [ 28 , 29 , 30 , 31 , 32 ]. Furthermore, S1R antagonists have the potential to counteract chemotherapy-induced peripheral neurotoxicity (CIPN), a pathologic condition that frequently occurs in cancer patients [ 33 , 34 , 35 ].…”