SA 4503 dihydrochloride

SA4503 dihydrochloride is a potent σ1 receptor agonist with an IC50 of 17.4 nM in guinea pig brain membranes.

In Vitro:The sigma receptor might be involved in several diseases in the central nervous system. SA4503, a potent σ1receptor agonist, has 103-fold higher affinity for σ1 (IC50=17.4 nM) than σ2 (IC50=1,784 nM) sites in guinea pig brain membranes. SA4503 is 14-fold selective for σ1 (Ki=4.6 nM) over σ2 (Ki=63.1 nM) sites in guinea pig brain homogenates[1]. 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]. SA4503 reduces the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1[3].

In Vivo:SA4503 extends the survival time in the SOD1G93A mice[2].

References:
[1]. Lever JR, et al. Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse. 2006 May;59(6):350-8. [2]. Tuerxun 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.

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.[Pubmed:17556637]

J Pharmacol Exp Ther. 2007 Sep;322(3):1305-14.

In the present study, we aimed to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the antidepressant-like effects of a sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503), in the olfactory bulbectomized (OB) rat model of depression. A symptomatology-based behavioral investigation was made by reconstructing in OB rats the symptoms of depression, such as psychomotor agitation, loss of interest, and cognitive dysfunction, using a typical antidepressant, desipramine, as a positive control. Repeated treatment with SA-4503 ameliorated the behavioral deficits in OB rats resembling depression symptoms in the open-field test, sexual behavior test, and cued and contextual fear-conditioning test. SA-4503 displayed advantages over desipramine in the sexual behavior test. SA-4503 also reversed the decrease in the protein expression of NMDA receptor subunit (NR)1, but not NR2A or NR2B, in the prefrontal cortex, hippocampus, and amygdala of OB rats. The behavioral and neurochemical effects of SA-4503 were blocked by combined treatment with a specific sigma(1) receptor antagonist, N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride (NE-100). Furthermore, the effects of SA-4503 on the performance of OB rats in the behavioral tests were abrogated by acute treatment with an NMDA receptor antagonist, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). The present study indicated for the first time that the sigma(1) receptor agonist SA-4503 may have effects on depressive symptoms such as agitation, loss of interest, and impaired cognition, which are mediated by NMDA receptors.

Stimulation of sigma1-receptor restores abnormal mitochondrial Ca(2)(+) mobilization and ATP production following cardiac hypertrophy.[Pubmed:23298811]

Biochim Biophys Acta. 2013 Apr;1830(4):3082-94.

BACKGROUND: We previously reported that the sigma1-receptor (sigma1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how sigma1R stimulation with the selective sigma1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through sigma1R localized in the sarcoplasmic reticulum (SR). METHODS: We first confirmed anti-hypertrophic effects of SA4503 (0.1-1muM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of sigma1R stimulation in vivo, we administered SA4503 (1.0mg/kg) and the sigma1R antagonist NE-100 (1.0mg/kg) orally to TAC mice for 4weeks (once daily). RESULTS: sigma1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72h impaired phenylephrine (PE)-induced Ca(2+) mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca(2+) mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72h decreased basal ATP content and PE-induced ATP production concomitant with reduced mitochondrial size, while SA4503 treatment completely restored ATP production and mitochondrial size. Pretreatment with NE-100 or siRNA abolished these effects. Chronic SA4503 administration also significantly attenuated myocardial hypertrophy and restored ATP production in TAC mice. SA4503 administration also decreased hypertrophy-induced impairments in LV contractile function. CONCLUSIONS: sigma1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca(2+) mobilization and ATP production via sigma1R stimulation. GENERAL SIGNIFICANCE: Our observations suggest that sigma1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction.

The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke.[Pubmed:21278085]

Brain. 2011 Mar;134(Pt 3):732-46.

Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.

Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503.[Pubmed:16463398]

Synapse. 2006 May;59(6):350-8.

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.

Binding properties of SA4503, a novel and selective sigma 1 receptor agonist.[Pubmed:8813641]

Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9.

The binding profiles of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel sigma receptor ligand, to sigma 1 and sigma 2 receptor subtypes in guinea pig and rat brain membranes were evaluated. SA4503 showed a high affinity for the sigma 1 receptor subtype labeled by (+)-[3H]pentazocine (IC50 = 17.4 +/- 1.9 nM), while it had about 100-fold less affinity for the sigma 2 receptor subtype labeled by [3H]1,3-di(2-tolyl)guanidine ([3H]DTG) in the presence of 200 nM (+)-pentazocine. SA4503 showed little affinity for 36 other receptors, ion channels and second messenger systems. The inhibition curves of SA4503 for (+)-[3H]pentazocine binding were shifted to the right in the presence of guanosine 5'-o-(3-thiotriphosphate) (GTP gamma S), as similar to those of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and (+)-pentazocine, sigma 1 receptor agonists. SA4503 significantly increased the KD value, but did not affect the Bmax value for specific (+)-[3H]pentazocine binding. These results indicated that SA4503 is a potent and selective agonist for the sigma 1 receptor subtype in the brain. In addition, SA4503 inhibited specific (+)-[3H]pentazocine binding in a competitive manner.

Cutamesine dihydrochloride (SA4503 dihydrochloride; AGY94806 dihydrochloride) is a potent Sigma 1 receptor agonist with an IC50 of 17.4 nM in guinea pig brain membranes.

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