Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

Abstract

Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10–45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09–1.82) and 2.31 (1.02–4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31–7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7–25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29–15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85–5.18) mg/kg, i.p.] in the 55°C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.

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

“…dose produced a singular increase in locomotor performance 60 min post-administration ( p = 0.003). Although the mechanism of σRs involvement in motor coordination and sedation has not yet been fully defined, the current results confirm the recent finding by Cirino et al, 35 showing that selective σ 1 R antagonists fail to produce sedative effects or impair evoked locomotor activity in rodents, confirming their analgesic properties.…”

“… 55 Currently, these studies with compound 15 verify previous findings stating that noxious stimuli are attenuated by σ 1 R antagonists. 35 , 48 , 56 …”

“… 57 To eliminate the potential complication of impaired locomotion or sedation, the effect of compound 15 on elicited locomotor activity was assessed using the rotarod assay. 35 The positive control and κ-opioid receptor agonist trans -(±)-3,4-dichloro- N -methyl- N -[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride (U50,488, 10 mg/kg, i.p.) significantly impaired evoked locomotor activity compared to the vehicle control ( F (4, 301) = 26.02; p < 0.0001; two-way ANOVA with Tukey’s post hoc test; Figure 5 ) up to 60 min after administration.…”

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

“…Respiration rates and spontaneous ambulation rates were monitored using the automated, computer-controlled Comprehensive Lab Animal Monitoring System (CLAMS, Columbus Instruments, Columbus, OH) as described previously ( Reilley et al, 2010 ; Cirino et al, 2019 ). Awake, freely moving adult male mice (C57BL6/J wild-type, MOR KO, and KOR KO) were habituated in closed, sealed individual apparatus cages (23.5 cm x 11/5 cm x 13 cm) for 60 min before testing.…”

Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

“…From their discovery, these receptors have attracted the attention of pharmacologists and medicinal chemists due to their pleiotropic functions on mitochondrial metabolism, apoptosis, ion channels modulation, lipid transport and metabolism regulation, neuritogenesis, mediation of Ca 2+ release, and interplays with G protein-coupled receptors (GPCRs) [24]. As a consequence, these receptors are involved in several pathological conditions, including SNC disorders (neuropathic pain, depression, Alzheimer's, Parkinson's) [25,26], and expressed in many types of cancer cells (e.g., prostate, breast, colorectal cancer, glioblastoma) [27,28]. Indeed, both the σ 1 R and the σ 2 R might have a critical role in cancer growth, cell proliferation, and tumor aggressiveness [29].…”