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℃ for 150 min or at 25℃ for 90 min.

Reaction Conditions

10^-12M-10^-3M Cutamesine (SA4503) at 37℃ for 150 min or at 25℃ for 90 min.

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 lines

Cultured cortical neurons( DIV4)

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.

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 models

Transgenic G93A [B6SJL-Tg (SOD1-G93A) 1Gur/J] mice

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

Dosage form

1 mg/kg Cutamesine (SA4503) once a day

Applications

Cutamesine (SA4503) prolonged the survival of SOD1 G93A mice

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.