σ1receptor （IC50 = 17.4 nM, guinea pig brain membranes)

The central nervous system is home to a number of disorders that may be related to the sigma receptor. In guinea pig brain membranes, cutamesine, a strong σ1receptor agonist, has a 103-fold greater affinity for σ1 (IC50=17.4 nM) sites than σ2 (IC50=1,784 nM). In guinea pig brain homogenates, cutamesine is 14-fold more selective for σ1 (Ki=4.6 nM) sites than σ2 (Ki=63.1 nM)[1]. Cutamesine shields motor neuron NSC34 cells from serum free neurotoxicity and superoxide dismutase 1. Extracellular signal-regulated kinase (ERK) 1/2 and Akt are both phosphorylated more highly by it[2]. Cutamesine downregulates the ionotropic glutamate receptor, GluR1, and lessens the activation of the MAPK/ERK pathway[3].

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cutamesine/SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, cutamesine/SA4503 is 14-fold selective for sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG >> (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK(i) values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined sigma(1)/sigma(2) binding selectivity.[1]

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Many studies suggest that antidepressants act as neuroprotective agents in the central nervous system (CNS), though the underlying mechanism has not been fully elucidated. In the present study, we examined the effect of cutamesine/SA4503, which is a sigma-1 receptor agonist and a novel antidepressant candidate, on oxidative stress-induced cell death in cultured cortical neurons. Exposure of the neurons to H(2)O(2) induced cell death, while pretreatment with SA4503 inhibited neuronal cell death. The SA4503-dependent survival effect was reversed by co-application with BD1047 (an antagonist of sigma-1/2 receptors). Previously we found that H(2)O(2) triggers a series of events including over-activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and intracellular Ca(2+) accumulation via voltage-gated Ca(2+) channels and ionotropic glutamate receptors, resulting in neuronal cell death (Numakawa et al. (2007) [20]). Importantly, we found in this study that SA4503 reduced the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1. Taking these findings together, it is possible that cutamesine/SA4503 blocks neuronal cell death via repressing activation of the MAPK/ERK pathway and, consequently, expression levels of glutamate receptors. [2]

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cutamesine reduced cell damage induced by light exposure in 661W cells [3]
We examined whether the cutamesine protected the 661W cells against light-induced cell death. Representative photographs of the Hoechst 33342 and PI staining of the 661W cells pretreated with cutamesine and/or BD-1047 are shown in Fig. 1A. Hoechst 33342 stains all cells (both live and dead), whereas PI stains only dead cells. Pretreatment with 10 μM cutamesine protected against light-induced cell death (Fig. 1B), and the protective effect significantly disappeared after treatment with BD-1047, a sigma-1 receptor antagonist, at 1 μM (Fig. 1C).

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Sigma-1 receptor expression was decreased by light exposure, and cutamesine recovered the expression in 661W cells [3]
To investigate the expression of sigma-1 receptor in 661W cells and the effect of cutamesine, we examined the western blot analysis. Sigma-1 receptor protein expressed in 661W cells, and the expression was significantly decreased by light exposure. Cutamesine at 10 μM significantly prevented the decreased expression of sigma-1 receptor protein (Fig. 2).

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cutamesine prevented the disruption of mitochondrial membrane potential [3]
We investigated whether cutamesine might prevent the disruption of the mitochondrial membrane potential. Healthy cells were detected with JC-1 J-aggregates (red fluorescent cells) and apoptotic or unhealthy cells were detected with JC-1 monomers (green fluorescent cells) (Fig. 3A). Light irradiation increased the numbers of green fluorescent 661W cells, indicating a disruption of the mitochondrial membrane potential. Cutamesine significantly reduced the number of green fluorescent cells, and BD-1047 significantly inhibited the effect of cutamesine (Fig. 3B).

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cutamesine prevented caspase-3/7 activation induced by light exposure [3]
To investigate the effect of cutamesine on caspase-3/7 activation induced by light irradiation, we measured caspase-3/7 activity using the Caspase-Glo 3/7 Assay System. Light irradiation significantly increased caspase-3/7 activity (Fig. 4). Cutamesine at 10 μM significantly reduced the activation of caspase 3/7, and this effect was attenuated by BD-1047 at 1 μM (Fig. 4).

In SOD1G93A mice, cutamesine prolongs their survival period[2].

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In in vivo studies, cutamesine suppressed the light-induced retinal dysfunction and thinning of the outer nuclear layer in the mouse retina. These findings indicate that cutamesine protects against retinal cell death in vitro and in vivo by the agonistic effect of sigma-1 receptor. Therefore, sigma-1 receptor may have a potential as a therapeutic target in retinal diseases mediated by photoreceptor degeneration.[3]

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cutamesine suppressed light-induced damage to retinal function and histological changes in mice [3]
The effects of cutamesine on light-induced retinal dysfunction were examined by electrophysiological analysis. The a-wave shows the function of the photoreceptors and the b-wave reflects the function of bipolar cells and Müller cells (Fig. 5A). Amplitudes of the a- and b-waves were significantly reduced five days after 8000 lux light exposure for 3 h. The decreases in the a- and b-wave amplitudes were significantly recovered by intravitreal injection of cutamesine (50 or 500 μM, 2 μL) compared with the vehicle-treated group (Fig. 5B).

Representative entire retinal images were obtained five days after light exposure for histological evaluation (Fig. 6A). The ONL was remarkably thinner in the light-irradiated retina than in the normal retina (Fig. 6A). cutamesine prevented the damage induced by light exposure (Fig. 6B). The thickness of the ONL was measured in 240-μm steps; the data were averaged and are shown in Fig. 6C. Cutamesine significantly protected the retinal damage in a dose-dependent manner. Furthermore, the protective effect of cutamesine (500 μM, 2 μL) on light-induced ONL thinning was significantly eliminated by co-administration with BD-1047 (500 μM), a sima-1 receptor antagonist (Fig. 7). On the other hand, BD-1047 alone did not show any effects on the light damages.

SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, SA4503 is 14-fold selective for sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG >> (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK(i) values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined sigma(1)/sigma(2) binding selectivity[1].

NSC34 cells are seeded at a density of 7000 cells per well into 96-well plates with D-MEM and transfected using Lipofectamine 2000 mixed with 2 μg /mL of plasmid vector in D-MEM for 6 h. After 6 h, the cell-culture medium is replaced with fresh D-MEM and culture and allowed to proceed for a further 42 h. The cells are then transferred to serum-free D-MEM and immediately treated with cutamesine at a final concentration of 1, 3, or 10 nM[2].

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The effects of cutamesine against white light-induced retinal photoreceptor damage were evaluated in vitro by measuring cell death. The expression of sigma-1 receptor after the light exposure was examined by immunoblot analysis. The disruption of the mitochondrial membrane potential and caspase-3/7 activation after excessive light exposure were also examined. In addition, retinal damage in mice induced by irradiation to white light was evaluated using histological staining and electroretinography. Cutamesine reduced the cell death rate induced by light exposure, and the protective effect was prevented by N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD-1047) dihydrobromide, a sigma-1 receptor antagonist. Sigma-1 receptor expression was decreased by light exposure, and cutamesine suppressed the decreased expression of sigma-1 receptor protein. Cutamesine also reduced the mitochondrial damage and reduced the elevated level of caspase 3/7 activity; this effect was attenuated by BD-1047.[3]

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Light-induced cell death model in 661W cell cultures [3]
The 661W cells were seeded at a density of 3 × 103 cells per well in 96-well plates, and then incubated for 24 h under a humidified atmosphere of 5% CO2 at 37 °C. Then, they were treated with 1 or 10 μM cutamesine and/or 1 μM N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD-1047) dihydrobromide and incubated for 1 h under a humidified atmosphere of 5% CO2 at 37 °C. The cells were exposed to 2500 lux of white fluorescent light for 24 h with each agent under a humidified atmosphere of 5% CO2 at 37 °C. The dark control cells and light-irradiated 661W cells were all from the same stock, eliminating any preexisting bias (such as light and temperature), as previously described by Kanan et al. (2007).

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Western blotting analysis [3]
The 661W cells were seeded at a density of 3 × 104 cells per well in 12-well plates, and then incubated for 24 h under a humidified atmosphere of 5% CO2 at 37 °C. Then, they were treated with 10 μM cutamesine and incubated for 1 h. The cells were exposed to 2500 lux of white fluorescent light for 24 h, then washed with PBS, lysed in RIPA buffer supplemented with 1% protease inhibitor cocktail and 1% phosphatase inhibitor cocktails 2 and 3, and harvested. The lysates were centrifuged at 12,000 g for 15 min at 4 °C. Protein concentrations were measured by comparison with a known concentration of bovine serum albumin, using a BCA Protein Assay Kit.

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Primary cortical cultures were prepared from postnatal 2-day-old rats as previously reported. The culture medium consisted of 5% fetal bovine serum, 5% heated-inactivated horse serum, 90% of a 1:1 mixture of Dulbecco's modified Eagle's medium, and Ham's F-12 medium. Dissociated cortical neurons were cultured for 4 or 5 days before cutamesine/SA4503 was applied. Twenty-four hours after SA4503 addition, H2O2 (final 50 μM) was applied for 12 h. Then, the cell viability was analyzed. To determine the cell viability, we carried out a mitochondrial-dependent conversion of the tetrazolium salt (MTT) assay. The metabolic activity of mitochondria was estimated with the MTT assay as previously reported. BD1047 (1 μM), an antagonist of sigma-1/2 receptors, was applied 20 min before adding SA4503. [2]

SOD1G93A mice: Transgenic female mice overexpressing mutated human SOD1G93A are used in the study. cutamesine is dissolved in saline and subcutaneously administered at a dose of 1 mg/kg once daily to 5-week-old SOD1G93A mice to the time of death. In a control group, vehicle (saline) is subcutaneously administered at 10 ml/kg[2].

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Exposure to visible light [3]
The mice were kept in dark conditions for 24 h prior to light exposure for dark adaptation. The pupils of the mice were dilated using 1% cyclopentolate hydrochloride eye drops 30 min prior to exposure to light. The mice, which were not anesthetized, were exposed to visible light (8000 lux) emitted by white fluorescent lamps for 3 h in cages with reflective interiors. The temperature during exposure to light was maintained at 25 ± 1.5 °C. After the exposure to light, all of the mice were returned to darkness for 24 h and then kept under normal light/dark cycling conditions. cutamesine (50 or 500 μM, injected volume; 2 μL), BD-1047 (500 μM), cutamesisne (500 μM) plus BD-1047 (500 μM), or PBS was injected into the intravitreal space 1 h prior to the light exposure. The concentrations of cutamesine in the vitreous body just after the intravitreal administration at 50 and 500 μM were estimated to be approximately 10 and 100 μM, respectively.

[1]. Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse. 2006 May;59(6):350-8.
[2]. SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression. Neurosci Lett. 2010 Jan 29;469(3):303-8.
[3]. Effect of a sigma-1 receptor agonist, cutamesine dihydrochloride (SA4503), on photoreceptor cell death against light-induced damage. Exp Eye Res. 2015 Mar;132:64-72.

Many studies have shown that antidepressants play a neuroprotective role in the central nervous system (CNS), but the underlying mechanisms have not been fully elucidated. This study investigated the effect of a novel antidepressant candidate drug, the σ-1 receptor agonist SA4503, on oxidative stress-induced cell death in cultured cortical neurons. H2O2 treatment can induce neuronal death, while SA4503 pretreatment can inhibit neuronal death. This cell survival effect of SA4503 can be reversed by combination with the σ-1/2 receptor antagonist BD1047. Our previous studies found that H₂O₂ triggers a series of events, including overactivation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and intracellular calcium accumulation through voltage-gated calcium channels and ionotropic glutamate receptors, ultimately leading to neuronal cell death (Numakawa et al., 2007) [20]. Importantly, this study found that SA4503 can reduce the activation of the MAPK/ERK pathway and downregulate the expression of the ionotropic glutamate receptor GluR1. Based on the above findings, SA4503 may block neuronal cell death by inhibiting the activation of the MAPK/ERK pathway, thereby reducing the expression level of glutamate receptors. [2]

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Catamethasone hydrochloride is an agonist of the σ-1 receptor, a ligand-activated receptor chaperone located on the mitochondrial-associated endoplasmic reticulum (ER) membrane. Endoplasmic reticulum stress plays a key role in light-induced retinal damage. In this study, we investigated the efficacy of catamethasone in vitro and in vivo in experimental retinal degeneration. [3]

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Nootropic drugs: Drugs used to specifically promote learning or memory, especially for the prevention of cognitive deficits associated with dementia. These drugs have diverse mechanisms of action.

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To elucidate the potential mechanisms of cutamesine/SA4503-dependent survival, we examined changes in the activation of intracellular signaling pathways. PI3K, phosphatidylinositol 3-kinase, and the MAPK/ERK pathway are essential for the survival of neurons in the central nervous system. On the other hand, we have previously reported that H2O2-induced ERK1/2 overactivation is associated with cell death. Therefore, to investigate the effect of MAPK/ERK pathway activation on the downstream effects of cutamesine/SA4503, we applied the MAPK/ERK pathway inhibitor U0126 to cortical cultures. U0126 (10 μM, 3 hours before H2O2 stimulation) significantly inhibited H2O2-dependent cell death (Fig. 2A), indicating that the MAPK/ERK pathway is involved in H2O2-induced cell death. Compared with SA4503 or U0126 alone, no additional or synergistic effects were observed with the combined application of U0126 and SA4503 (Fig. 2A), suggesting that the reduction in MAPK/ERK pathway activation contributes to the cytoprotective effect of SA4503. We confirmed that after U0126 treatment (3 hours), the activation (phosphorylation) of p44/42 MAPK (ERK1/2) decreased in a dose-dependent manner, but the total expression level of ERK1/2 remained unchanged (Fig. 2B). Next, we examined the activation of ERK1/2 after SA4503 treatment. After 0.5–3 hours of SA4503 treatment, pERK1/2 levels decreased (Figure 2C). SA4503 treatment did not alter the total expression level of ERK1/2 (Figure 2C). SA4503 inhibited pERK1/2 levels in a dose-dependent manner (Figure 2D). We also examined the activation of Akt (a component of the PI3K pathway). When determining the time- or dose-dependent effect of SA4503 on Akt activation, we found that Akt activation levels were unaffected by SA4503 (Figures 2E and F). Total Akt expression levels remained intact after SA4503 treatment (Figures 2E and F). Furthermore, we examined total JNK1/2 (c-JunNH2 terminal kinase 1/2, another member of the MAPK family) and pJNK1/2 (which regulate apoptosis). After determining the time or dose dependence of SA4503, the results showed that the levels of total JNK1/2 and pJNK1/2 were not affected by SA4503 (Fig. 2G and H). These results suggest that SA4503 has a protective effect on cortical neurons by inhibiting the activation of the MAPK/ERK pathway. [2] In summary, as a sig-1R agonist, SA4503 promotes the survival of cultured cortical neurons. Previously, we found that antidepressants (imipramine and fluvoxamine) can enhance BDNF-induced intracellular signaling by stimulating sig-1R, thereby promoting the release of glutamate. Recently, it has been reported that long-term use of SA4503 can upregulate the expression of BDNF protein in the hippocampus of rats. In summary, these results, including our current study, suggest that SA4503 plays multiple roles in the central nervous system. In addition to its potential as a novel antidepressant, SA4503 may also have value in treating neurodegenerative diseases of the central nervous system, but further research is needed on its intracellular mechanisms. [2]

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cutamesine dihydrochloride is an agonist of the σ-1 receptor, a ligand-activated receptor chaperone located on the mitochondrial-associated endoplasmic reticulum (ER) membrane. ER stress plays a crucial role in light-induced retinal damage. In this study, we investigated the efficacy of cutamesine in vitro and in vivo against experimental retinal degenerative damage. We assessed the in vitro effects of cutamesine on white light-induced retinal photoreceptor damage by measuring cell death. σ-1 receptor expression after light exposure was detected by immunoblotting. This study also examined the disruption of mitochondrial membrane potential and caspase-3/7 activation after excessive light exposure. Furthermore, retinal damage in mice exposed to white light was assessed using histological staining and electroretinography. The results showed that cutamesine reduced light-induced cell death, and its protective effect was blocked by the σ-1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD-1047) dihydrobromide. Light exposure reduced the expression of σ-1 receptors, and cutamesine inhibited the reduction of σ-1 receptor protein expression. Cutamesine also alleviated mitochondrial damage and reduced caspase-3/7 activity levels; BD-1047 attenuated the above effects of cutamesine. In vivo studies showed that cutamesine inhibited light-induced dysfunction and thinning of the outer nuclear layer in the mouse retina. These findings suggest that cutamesine protects retinal cells from death in vitro and in vivo by activating σ-1 receptors. Therefore, σ-1 receptors may have the potential to be a therapeutic target for photoreceptor degeneration-mediated retinal diseases. [3]

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In this study, we investigated whether the σ-1 receptor agonist cutamesine has a protective effect against light-induced retinal damage in vitro and in vivo. To investigate the effect of cutamesine on photoinduced cell death in 661W cells (mouse photoreceptor-derived cells), we measured cell death rate using nuclear staining. 10 μM cutamesine significantly reduced photoinduced cell death. This protective effect was inhibited by the σ-1 receptor antagonist BD-1047. These results indicate that, in vitro, cutamesine protects against photoinduced photoreceptor cell death via the σ-1 receptor. Previously, the expression of the σ-1 receptor in photoreceptor cells had been confirmed in in vivo models (Mavlyutov et al., 2011). Our results confirm the expression of the σ-1 receptor in 661W cells. Light exposure reduces its expression, and cutamesine attenuates this expression. σ-1 receptor downregulation has been reported in various models. For example, the endoplasmic reticulum stress inducer tunicamycin reduces σ-1 receptor protein expression in HT22 cells, while imipramine inhibits this downregulation (Ono et al., 2012). In another example, the downregulation of σ-1 receptors in the heart caused by transverse aortic constriction can be attenuated by the σ-1 receptor agonist fluvoxamine (Tagashira et al., 2010). These studies suggest that σ-1 receptor agonists have a stabilizing or upregulating effect on σ-1 receptors. Therefore, in this study, cutamesine may have a stabilizing or upregulating effect on σ-1 receptors. Next, we investigated the effect of cutamesine on mitochondrial membrane potential disturbances. The results showed that cutamesine was able to restore mitochondrial membrane potential disturbances, while BD-1047 inhibited this effect of cutamesine. These results indicate that cutamesine activates σ-1 receptors and enhances their function, thereby restoring abnormal mitochondrial Ca2+ levels, which is consistent with previous reports from another research group (Tagashira et al., 2013). Therefore, the protective effect of cutamesine against photodamage may depend on the restoration of mitochondrial function. Activation of the cell death effector caspase-3 has been reported in photoreceptors in animal models of retinal degeneration (Jomary et al., 2001). Abnormal mitochondrial Ca2+ levels can also mediate caspase-3 activation via cytochrome c release (He et al., 2000). In this study, white fluorescent light irradiation induced caspase 3/7 activation in 661W cells. Cutamesine reduced this elevated level, while BD-1047 blocked this effect. These reports suggest that cutamesine inhibits caspase activity by restoring mitochondrial function. Finally, we investigated the protective effect of cutamesine against photoinduced damage in an in vivo mouse model. Intravitreal injection of 50 μM and 500 μM cutamesine inhibited photoinduced damage and changes in retinal function and histology in mice. Following intravitreal injection, the concentrations of cutamesine in the vitreous body were approximately 10 μM and 100 μM, respectively. Its protective effect was similar to that of the effective concentration of 10 μM in vitro. Furthermore, co-administration of cutamesine with the σ-1 receptor antagonist BD-1047 eliminated the protective effect of cutamesine against photoinduced damage. Therefore, this effect may depend on the activation of σ-1 receptor proteins, leading to mitochondrial normalization and inhibition of caspase activity, as demonstrated in this in vitro study. We recently reported that light exposure causes excessive endoplasmic reticulum stress and induces photoreceptor cell death by activating the C/EBP homolog (CHOP)-dependent apoptosis pathway (Nakanishi et al., 2013). Li et al. (2009) also reported that endoplasmic reticulum stress leads to CHOP-mediated macrophage apoptosis through pathways involving endoplasmic reticulum calcium release and mitochondrial release of apoptosis factors, suggesting that CHOP-dependent apoptosis is associated with mitochondrial dysfunction. Furthermore, in our previous study, imipramine inhibited hippocampal HT22 cell death by restoring downregulated σ-1 receptors to normal without altering the elevated expression of CHOP (Ono et al., 2012). In this study, cutamesine may have protected 661W cells from death by restoring downregulated σ-1 receptors to normal. As another possible mechanism, we previously reported that cutamesine can activate extracellular signal-regulated kinases (ERK) 1/2 and Akt in mouse motor neuron (NSC34) cells, both of which are survival factors (Ono et al., 2014). Excessive exposure to visible light can also induce its inactivation via ERK dephosphorylation (Kuse et al., 2014). Furthermore, Fujimoto et al. (2012) reported that cutamesine can enhance the post-translational processing of neurotrophic factors such as BDNF and GDNF by preventing the misfolding of secreted proteins in the endoplasmic reticulum: σ-1 receptors are thought to regulate protein folding as molecular chaperones in the endoplasmic reticulum. Therefore, the above mechanisms may also be related to the protective effect of cutamesine. In summary, cutamesine protects the retina from light-induced photoreceptor cell death by restoring the expression of σ-1 receptor proteins and enhancing the stimulatory effect of σ-1 receptors. Therefore, these findings may provide evidence for a novel role of cutamesine in combating light-induced retinal damage, suggesting its potential therapeutic value in treating retinal diseases mediated by photoreceptor degeneration. [3]

C₂₃H₃₄CL₂N₂O₂

441.43

440.199

C, 62.58; H, 7.76; Cl, 16.06; N, 6.35; O, 7.25

165377-44-6

Cutamesine;165377-43-5

9954941

White to off-white solid powder

499.2ºC at 760 mmHg

137.3ºC

4.25E-10mmHg at 25°C

4.976

2

4

9

29

392

0

Cl[H].Cl[H].O(C([H])([H])[H])C1=C(C([H])=C([H])C(=C1[H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])C1([H])[H])OC([H])([H])[H]

XWOXAKBQEMQMFH-UHFFFAOYSA-N

InChI=1S/C23H32N2O2.2ClH/c1-26-22-11-10-21(19-23(22)27-2)12-14-25-17-15-24(16-18-25)13-6-9-20-7-4-3-5-8-20;;/h3-5,7-8,10-11,19H,6,9,12-18H2,1-2H3;2*1H

1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine;dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 33.33 mg/mL (75.50 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)