S1RA

S1RA is a potent and selective antagonist of σ1 receptor (σ1R) with Ki value of 17nM [1].

S1RA is the first σ1 receptor antagonist with potent antinociceptive activities in various pain models. In the binding assay, S1RA shows good affinity to human σ1 receptor transfected in HEK293 membranes with Ki value of 17nM. The Ki value for guinea pig brain membrane σ1 receptor is higher than 1μM. S1RA also shows no significant affinity to another 170 molecular targets including receptors, ion channels and enzymes [1, 2].

In the mouse tests, S1RA exhibits potent analgesic effects on capsaicin-induced mechanical hypersensitivity and formalin-induced pain. Besides that, S1RA inhibits both mechanical allodynia and thermal hypersensitivity with ED50 values of 23.4mg/kg and 18.8mg/kg in the partial sciatic nerve ligation model in mice [1].

References:
[1] Díaz J L, Cuberes R, Berrocal J, et al. Synthesis and Biological Evaluation of the 1-Arylpyrazole Class of σ1 Receptor Antagonists: Identification of 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1 H-pyrazol-3-yloxy] ethyl} morpholine (S1RA, E-52862). Journal of medicinal chemistry, 2012, 55(19): 8211-8224.
[2] Wunsch B. The σ1 Receptor Antagonist S1RA Is a Promising Candidate for the Treatment of Neurogenic PainJ. Journal of medicinal chemistry, 2012, 55(19): 8209-8210.

Effects of the selective sigma-1 receptor antagonist S1RA on formalin-induced pain behavior and neurotransmitter release in the spinal cord in rats.[Pubmed:24384038]

J Neurochem. 2014 May;129(3):484-94.

We have previously shown that the selective sigma-1 receptor (sigma1 R) antagonist S1RA (E-52862) inhibits neuropathic pain and activity-induced spinal sensitization in various pre-clinical pain models. In this study we characterized both the behavioral and the spinal neurochemical effects of S1RA in the rat formalin test. Systemic administration of S1RA produced a dose-related attenuation of flinching and lifting/licking behaviors in the formalin test. Neurochemical studies using concentric microdialysis in the ipsilateral dorsal horn of awake, freely moving rats revealed that the systemic S1RA-induced antinociceptive effect occurs concomitantly with an enhancement of noradrenaline levels and an attenuation of formalin-evoked glutamate release in the spinal dorsal horn. Intrathecal pre-treatment with idazoxan prevented the systemic S1RA antinociceptive effect, suggesting that the S1RA antinociception depends on the activation of spinal alpha2 -adrenoceptors which, in turn, could induce an inhibition of formalin-evoked glutamate release. When administered locally, intrathecal S1RA inhibited only the flinching behavior, whereas intracerebroventricularly or intraplantarly injected also attenuated the lifting/licking behavior. These results suggest that S1RA supraspinally activates the descending noradrenergic pain inhibitory system, which may explain part of its antinociceptive properties in the formalin test; however, effects at other central and peripheral sites also account for the overall effect. Formalin-induced nociceptive effect occurs concomitantly with an enhancement of glutamate (Glu) level in the dorsal horn spinal cord. The selective sigma1 receptor antagonist S1RA results in inhibition of formalin-evoked Glu release, no modification of GABA levels, and enhancement of noradrenaline (NA) levels. This increased spinal NA activates spinal alpha2-adrenoceptors producing the attenuation of the formalin-induced pain behaviour.

Analysis of the molecular interactions of the potent analgesic S1RA with the sigma1 receptor.[Pubmed:23582276]

Bioorg Med Chem Lett. 2013 May 15;23(10):2868-71.

The highly selective sigma1 receptor antagonist S1RA is endowed with a surprisingly high affinity for its target protein given a missing fundamental hydrophobic pharmacophoric requirement. Here we show that, with respect to other potent sigma1 ligands, S1RA is able to compensate this loss by fulfilling all other pharmacophoric requirements and by gaining in solvation energy.

S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice.[Pubmed:24776490]

Behav Pharmacol. 2014 Jun;25(3):226-35.

The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (sigma1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well-characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. Morphine also showed maximum efficacy in all tests. Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to sigma1R knockout mice, thus suggesting the involvement of sigma1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain.

S1RA(E-52862) is a potent and selective sigma-1 receptor(σ1R, Ki=17 nM) antagonist, showed good selectivity against σ2R (Ki > 1000 nM).

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