S1RA (E-52862) is a highly selective σ1 receptor (σ1R) antagonist with Kis of 17 nM and 23.5 nM for human σ1R and guinea pig σ1R, respectively. Its activity extends moderately towards the human 5-HT2B receptor with a Ki of 328 nM. This selectivity profile is complemented by its antinociceptive capabilities in models of neuropathic pain, demonstrating efficacy in preventing both mechanical and cold hypersensitivity in mice treated with Oxaliplatin[1][2].
体内研究
In vivo, a single intraperitoneal (IP) dose of S1RA at 40 mg/kg leads to a significant reduction in pain responses induced by Allylisothiocyanate (AITC) in wild-type (WT) mice. Further demonstrating its analgesic potential, the same dosing regimen, administered once daily for 11 days starting 3 days before Oxaliplatin injection, effectively counters mechanical and cold hypersensitivity induced by the chemotherapy agent Oxaliplatin in mice[2].
体外研究
In cell-based assays, S1RA at a concentration of 100 µM over 4 hours can inhibit intracellular calcium responses in TRPA1-expressing HEK293 cells, illustrating its potential for modulating ion channel activities. It also impairs the formation of TRPA1–Sigma-1R complexes and reduces TRPA1 expression at the plasma membrane, which could underlie some of its therapeutic effects[2].
S1RA 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Androgen negative human prostate cancer cells DU145
4.0-5.5 µM
72 hours
Inhibited the growth of DU145 tumor cells more effectively than the reference σ1 antagonists NE100 and S1RA
ChemMedChem. 2022 Apr 5;17(7):e202100735
S1RA 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Spinal cord contusion model
Intraperitoneal injection
10, 20, 40, 60 mg/kg
Single dose, evaluated after 30 minutes
To evaluate the effect of S1RA on mechanical allodynia and thermal hyperalgesia after spinal cord contusion. Results showed that S1RA dose-dependently reversed both mechanical allodynia and thermal hyperalgesia.
Sci Rep. 2018 Mar 1;8(1):3873
Sprague-Dawley rats
Novel object recognition test
Intraperitoneal injection
15 and 30 mg/kg
Single dose, tested 30 minutes after administration
Evaluated the role of S1RA in cognitive function; results showed S1RA as a σ1R antagonist did not improve learning and memory
Pharmacol Rep. 2023 Oct;75(5):1291-1298
Mice
Formalin-induced pain model
Intraperitoneally (i.p.)
15 mg/kg
Single administration, tested 30 min after administration
Evaluated the analgesic effect of S1RA in the formalin-induced pain model, showing significant reduction in nociceptive response in the late phase
Pharmaceuticals (Basel). 2023 Oct 17;16(10):1481
CD1 mice
Partial sciatic nerve ligation-induced neuropathic pain model
Intraperitoneal injection
16, 32, 64 mg/kg
Single dose
To evaluate the inhibitory effect of S1RA on neuropathic pain
Br J Pharmacol. 2012 Aug;166(8):2289-306
Mice
Σ2R−/− and σ1R−/− mice
Intracerebroventricular injection
3 nmol
Single administration
S1RA increased the analgesic activity of morphine in both σ2R?/? and wild-type mice.
Mol Brain. 2020 Nov 11;13(1):150
CD1 mice
Permanent middle cerebral artery occlusion (pMCAO) model
Intracerebroventricular (icv) or intravenous (iv) injection
3 nmol/mouse (icv) or 30 μg/mouse (iv)
Up to 5 h before surgery and 3 h after ischaemic onset
S1RA significantly reduced cerebral infarct volume, ameliorated neurological deficits, and suppressed the overexpression of MMP-9 and reactive astrogliosis.
Mol Neurobiol. 2018 Jun;55(6):4940-4951
Rats
Tail-flick test
Intraperitoneal injection
40 mg/kg
Single administration, observation time up to 300 minutes
To evaluate the enhancement of systemic morphine antinociception by S1RA. Results showed that S1RA alone had no antinociceptive effect but significantly enhanced the antinociceptive effect of morphine when co-administered.
Front Pharmacol. 2019 Apr 24;10:422
Mice
CFA-induced periarticular inflammation model
Subcutaneous injection
80 mg/kg
Single or multiple administrations
S1RA alone did not affect nociceptive heat pain or inflammatory tactile allodynia but partially reversed grip strength deficits. When combined with morphine, S1RA significantly enhanced morphine's analgesic effects on heat stimuli and inflammatory tactile allodynia but not on grip strength deficits. In morphine-tolerant animals, S1RA restored the analgesic effects of morphine.
Front Pharmacol. 2019 Feb 22;10:136
Mice
Spared nerve injury (SNI) model
Subcutaneous injection
8–128 mg/kg
Acute administration: single dose; Repeated administration: twice daily for 10 days
S1RA alleviated SNI-induced neuropathic pain through σ1 receptor antagonism, with effects partially dependent on the endogenous opioid system.
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