Cutamesine (SA4503)
(Synonyms: 1-[2-(3,4-二甲氧基苯基)乙基]-4-(3-苯基丙基)哌嗪,SA4503; AGY 94806) 目录号 : GC33697
Cutamesine (SA4503) 是大脑中 sigma 1 受体亚型的有效选择性激动剂。
Cas No.:165377-43-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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| Kinase experiment [1]: | |
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Preparation Method |
Cutamesine (SA4503) Binding affinities to sigma-1，2 receptor subtypes were assessed with 5 nM (+)-[3H]pentazocine or 5 nM [3H]DTG with 200 nM (+)-[3H]pentazocine. Incubations in the (+)-[3H]pentazocine and [3H]DTG binding studies were carried out at 37°C for 150 min or at 25°C for 90 min. |
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Reaction Conditions |
10-12M-10-3M Cutamesine (SA4503) at 37°C for 150 min or at 25°C for 90 min. |
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Applications |
Competition binding experiments showed that Cutamesine (SA4503) had a high affinity for (+)-[Hlpentazocine binding sites in guinea pig brain membranes . The IC50 value of this compound for the sigma-1 receptor subtype was 17.4 + 1.9 nM. Cutamesine (SA4503) had a low affinity for the sigma-2 receptor subtype, with an IC50 value of1784.1 + 314.4 nM. The inhibitory potency of Cutamesine (SA4503) for the sigma-1 receptor subtype was about 100 times higher than that for the sigma-2 receptor subtype. |
| Cell experiment [2]: | |
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Cell lines |
Cultured cortical neurons( DIV4) |
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Preparation Method |
Dissociated cortical neurons were cultured for 4 or 5 days before Cutamesine (SA4503) was applied. Twenty-four hours after Cutamesine (SA4503) addition, H202 was applied for 12 h. Then, the cell viability was analyzed. |
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Applications |
Cutamesine (SA4503) prevents cultured cortical neurons from cell death caused by H2O2 application. The survival effect by Cutamesine (SA4503) reached a plateau at 0.1 μM. |
| Animal experiment [3]: | |
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Animal models |
Transgenic G93A [B6SJL-Tg (SOD1-G93A) 1Gur/J] mice |
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Preparation Method |
Cutamesine (SA4503) was dissolved in saline and subcutaneously administered at a dose of 1 mg/kg once daily to 5-week-old mice to the time of death |
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Dosage form |
1 mg/kg Cutamesine (SA4503) once a day |
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Applications |
Cutamesine (SA4503) prolonged the survival of SOD1 G93A mice |
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References: [1]. Matsuno K, Nakazawa M, et,al. Binding properties of SA4503, a novel and selective sigma 1 receptor agonist. Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9. doi: 10.1016/0014-2999(96)00201-4. PMID: 8813641. [2]. Tuerxun T, Numakawa T, et,al. 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. doi: 10.1016/j.neulet.2009.12.013. Epub 2009 Dec 16. PMID: 20025928. [3]. Ono Y, Tanaka H, et,al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett. 2014 Jan 24;559:174-8. doi: 10.1016/j.neulet.2013.12.005. Epub 2013 Dec 12. PMID: 24334165. |
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Cutamesine (SA4503) is a potent and selective agonist for the sigma 1 receptor subtype in the brain. Cutamesine (SA4503) inhibited specific (+)-[3H]pentazocine binding in a competitive manner(IC50 = 17.4 +/- 1.9 nM) in guinea pig meninges[1，4].
Cutamesine (SA4503) prevents cultured cortical neurons from cell death caused by H2O2 application. The survival effect by Cutamesine (SA4503) reached a plateau at 0.1 μM[3]. Cutamesine(SA4503) reduces the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1[2]. Cutamesine(SA4503) protects motor neuron NSC34 cells against superoxide dismutase 1 and serum free neurotoxicity. It upregulates the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) 1/2 [2].
Cutamesine (SA4503) extended the survival time, but it did not delay the disease onset in the SOD1G93A mice. The extended survival time in the Cutamesine (SA4503) group may be associated with the suppression of the progression of motor neuron damage by the upregulation of phosphorylated Akt and ERK1/2. From these results, Cutamesine (SA4503) may have the protective effect against FALS, because SOD1G93A mice are model of FALS [2]. When examined the effects of Cutamesine (SA4503) on the cholinergic dysfunction-induced memory impairments in a passive avoidance task. Single administration of Cutamesine (SA4503) significantly reduced the scopolamine-induced memory impairment [5]. Cutamesine (SA4503) produced a significant decrease and rise in the number of spontaneously active SNC and VTA DA neurons in rats. Cutamesine (SA4503) produced a significant increase in the number of spontaneously active VTA DA neurons relative to SNC DA neurons Repeated administration of Cutamesine (SA4503) produced a greater change in the firing pattern of spontaneously active VTA[6]. Repeated treatment with Cutamesine (SA4503) (0.3 mg/kg) improved the behavior disorder similar to depressive symptoms in rats in olfactory bulb resection group. Cutamesine (SA4503) also reversed the reduction of NMDA receptor subunit (NR)1 protein expression in the prefrontal cortex, hippocampus, and amygdala of olfactory bulbectomy rats, but did not affect NR2A or NR2B[7].
References:
[1]: Lever JR, Gustafson JL, et,al. Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse. 2006 May;59(6):350-8. doi: 10.1002/syn.20253. PMID: 16463398.
[2]: Ono Y, Tana19996ka H, et,al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett. 2014 Jan 24;559:174-8. doi: 10.1016/j.neulet.2013.12.005. Epub 2013 Dec 12. PMID: 24334165.
[3]: Tuerxun T, Numakawa T, et,al. 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. doi: 10.1016/j.neulet.2009.12.013. Epub 2009 Dec 16. PMID: 20025928.
[4]: Matsuno K, Nakazawa M, et,al.Binding properties of SA4503, a novel and selective sigma 1 receptor agonist. Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9. doi: 10.1016/0014-2999(96)00201-4. PMID: 8813641.
[5]: Senda T, Matsuno K, et,al. Ameliorating effect of SA4503, a novel sigma 1 receptor agonist, on memory impairments induced by cholinergic dysfunction in rats. Eur J Pharmacol. 1996 Nov 7;315(1):1-10. doi: 10.1016/s0014-2999(96)00572-9. PMID: 8960858.
[6]: Minabe Y, Matsuno K, et,al. Acute and chronic administration of the selective sigma1 receptor agonist SA4503 significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study. Synapse. 1999 Aug;33(2):129-40. doi: 10.1002/(SICI)1098-2396(199908)33:23.0.CO;2-E. PMID: 10400891.
[7]: Wang D, Noda Y, et,al. Role of N-methyl-D-aspartate receptors in antidepressant-like effects of sigma 1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503) in olfactory bulbectomized rats. J Pharmacol Exp Ther. 2007 Sep;322(3):1305-14. doi: 10.1124/jpet.107.124685. Epub 2007 Jun 7. PMID: 17556637.
Cutamesine (SA4503) 是大脑中 sigma 1 受体亚型的有效选择性激动剂。 Cutamesine (SA4503) 在豚鼠脑膜中以竞争性方式抑制特异性 (+)-[3H]pentazocine 结合 (IC50 = 17.4 +/- 1.9 nM)[1，4]< /sup>.
Cutamesine (SA4503) 可防止培养的皮层神经元因 H2O2 应用而导致细胞死亡。 Cutamesine (SA4503) 的存活效应在 0.1 μM[3] 时达到稳定水平。 Cutamesine(SA4503) 可降低 MAPK/ERK 通路的激活并下调离子型谷氨酸受体 GluR1[2]。 Cutamesine (SA4503) 保护运动神经元 NSC34 细胞免受超氧化物歧化酶 1 和无血清神经毒性。它上调Akt和细胞外信号调节激酶（ERK）1/2的磷酸化水平[2]。
Cutamesine (SA4503) 延长了 SOD1G93A 小鼠的存活时间，但并未延迟疾病发作。 Cutamesine (SA4503) 组的延长生存时间可能与通过上调磷酸化 Akt 和 ERK1/2 抑制运动神经元损伤的进展有关。从这些结果来看，Cutamesine (SA4503) 可能对 FALS 具有保护作用，因为 SOD1G93A 小鼠是 FALS 的模型[2]。当检查 Cutamesine (SA4503) 对被动回避任务中胆碱能功能障碍引起的记忆障碍的影响时。单次服用 Cutamesine (SA4503) 可显着降低东莨菪碱诱导的记忆障碍[5]。 Cutamesine (SA4503) 使大鼠自发活跃的 SNC 和 VTA DA 神经元数量显着减少和增加。相对于 SNC DA 神经元，Cutamesine (SA4503) 显着增加了自发活跃的 VTA DA 神经元的数量重复给予 Cutamesine (SA4503) 在自发活跃的 VTA 放电模式中产生了更大的变化[6]。 Cutamesine (SA4503) (0.3 mg/kg)重复治疗改善了嗅球切除组大鼠类似抑郁症状的行为障碍。 Cutamesine (SA4503) 还可以逆转嗅球切除术大鼠前额皮质、海马和杏仁核中 NMDA 受体亚基 (NR)1 蛋白表达的减少，但不影响 NR2A 或 NR2B[7]。
| Cas No. | 165377-43-5 | SDF | |
| 别名 | 1-[2-(3,4-二甲氧基苯基)乙基]-4-(3-苯基丙基)哌嗪,SA4503; AGY 94806 | ||
| Canonical SMILES | COC1=CC=C(CCN2CCN(CCCC3=CC=CC=C3)CC2)C=C1OC | ||
| 分子式 | C23H32N2O2 | 分子量 | 368.51 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7136 mL | 13.5682 mL | 27.1363 mL |
| 5 mM | 0.5427 mL | 2.7136 mL | 5.4273 mL |
| 10 mM | 0.2714 mL | 1.3568 mL | 2.7136 mL |
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Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy
Mol Imaging Biol 2015 Jun;17(3):364-72.PMID:25449772DOI:10.1007/s11307-014-0808-2.
Purpose: Rapid eye movement (REM) sleep deprivation (SD) decreases cerebral sigma-1 receptor expression and causes cognitive deficits. Sigma-1 agonists are cognitive enhancers. Here, we investigate the effect of Cutamesine treatment in the REM SD model. Procedures: Sigma-1 receptor occupancy (RO) in the rat brain by Cutamesine was determined using 1-[2-(3,4-dimethoxyphenethyl)]-4-(3-phenylpropyl)piperazine ([(11)C]SA4503) and positron emission tomography (PET), and tissue Cutamesine levels were measured by ultra performance liquid chromatography (UPLC)-MS. RO was calculated from a Cunningham-Lassen plot, based on the total distribution volume of [(11)C]SA4503 determined by Logan graphical analysis. Cognitive performance was assessed using the passive avoidance (PA) test. Results: Cutamesine at a dose of 1.0 mg/kg reversed REM SD-induced cognitive deficit and occupied 92 % of the sigma-1 receptor population. A lower dose (0.3 mg/kg) occupied 88 % of the receptors but did not significantly improve cognition. Conclusion: The anti-amnesic effect of Cutamesine in this animal model may be related to longer exposure at a higher dose and/or drug binding to secondary targets.
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.PMID:25616094DOI:10.1016/j.exer.2015.01.017.
Cutamesine dihydrochloride is an agonist of sigma-1 receptor, which is a ligand-operated receptor chaperone at the mitochondrion-associated endoplasmic reticulum (ER) membrane. ER stress plays a pivotal role in light irradiation-induced retinal damage. In the present study, we examined whether Cutamesine is effective against experimental degenerative retinal damages in vitro and in vivo. 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. 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.
Phase II trial of the Sigma-1 receptor agonist Cutamesine (SA4503) for recovery enhancement after acute ischemic stroke
Stroke 2014 Nov;45(11):3304-10.PMID:25270629DOI:10.1161/STROKEAHA.114.005835.
Background and purpose: The σ-1 receptor (Sig-1R) agonist Cutamesine (SA4503) enhanced functional recovery after experimental stroke with a treatment initiation window of 48 hours and chronic treatment for 28 days. We conducted a phase 2 clinical trial exploring the safety, tolerability, dose range, and functional effects of cutamesine in patients with ischemic stroke. Methods: Subjects were randomized between 48 and 72 hours after stroke to receive cutamesine 1 mg/d, 3 mg/d, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (day 28), and at end of follow-up (day 56). Results: In 60 patients, treatment with both cutamesine dosages was safe and well tolerated without significant differences in numbers of treatment emergent or serious adverse events. No significant effect was observed on the primary efficacy measure (change in National Institutes of Health Stroke Scale from baseline to day 56) or modified Rankin Scale and Barthel Index scores. Post hoc analysis of moderately and severely affected patients (baseline National Institutes of Health Stroke Scale, ≥7 and ≥10) showed greater National Institutes of Health Stroke Scale improvements in the 3 mg/d cutamesine group when compared with placebo (P=0.034 and P=0.038, respectively). A trend toward a higher proportion being able to complete a 10m timed walk was observed for cutamesine-treated subjects. Conclusions: Cutamesine was safe and well tolerated at both dosage levels. Although no significant effects on functional end points were seen in the population as a whole, greater improvement in National Institutes of Health Stroke Scale scores among patients with greater pretreatment deficits seen in post hoc analysis warrants further investigation. Additional studies should focus on the patient population with moderate-to-severe stroke. Clinical trial registration url: http://www.clinicaltrials.gov/show/NCT00639249. Unique identifier: NCT00639249. The EudraCT number is 2007-004840-60 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004840-60/GB).
Inhibitory effects of SA4503 on the rewarding effects of abused drugs
Addict Biol 2014 May;19(3):362-9.PMID:22934790DOI:10.1111/j.1369-1600.2012.00488.x.
Previous findings have shown that sigma-1 receptors (Sig-1Rs) are upregulated by the self-administration of methamphetamine, whereas Sig-1R antisense can attenuate the behavioral effects of psychostimulants in rodents. Sig-1R is an endoplasmic reticulum chaperone protein. However, the effects of Sig-1R agonist on the rewarding effects of abused drugs are not fully understood. Therefore, we examined the effects of selective Sig-1R agonists, such as SA4503 and (+)-pentazocine, on the rewarding effects of abused drugs such as methamphetamine, cocaine and morphine in rats, as measured by the conditioned place preference. Methamphetamine, cocaine and morphine induced a significant place preference. SA4503, but not (+)-pentazocine, significantly attenuated the abused drug-induced place preference. We recently showed that (+)-pentazocine exerts U50,488H-like discriminative stimulus effects, which are related to its psychotomimetic/aversive effects. However, SA4503 did not generalize to the discriminative stimulus effects of U50,488H. These results suggest that SA4503 inhibits the rewarding effects of abused drugs, and that psychotomimetic/aversive effects may not play a role in the attenuating effects of SA4503 on the rewarding effects of abused drugs.
Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases
Curr Pharm Des 2012;18(7):875-83.PMID:22288409DOI:10.2174/138161212799436476.
Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as schizophrenia and psychotic depression. The drugs currently used to treat cognitive impairment have significant limitations, ensuring that the search for more effective therapies remains active. Endoplasmic reticulum protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil and neurosteroids. Among SSRIs, fluvoxamine, a potent sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors. Sigma-1 receptor agonists greatly potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia is significantly improved by sub-chronic administration of sigma-1 receptor agonists such as fluvoxamine, SA4503 (Cutamesine) and donepezil. This effect is antagonized by co-administration of NE-100. A positron emission tomography (PET) study using the specific sigma-1 receptor ligand [11C]SA4503 demonstrates that fluvoxamine and donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on sigma-1 receptor agonists as potential therapeutic drugs for the treatment of cognitive impairment in schizophrenia and psychotic depression.