SA 4503 dihydrochloride is a highly selective σ1 receptor agonist with an IC50 value of 17nM[1]. The σ1 receptor is a molecular chaperone protein primarily located in the endoplasmic reticulum of central nervous system cells and plays a key role in maintaining cellular homeostasis, regulating ion channels (such as calcium and sodium channels), and providing neuroprotection[2, 3]. SA 4503 dihydrochloride is commonly used in the treatment and research of various neurological (such as Parkinson's disease and depression) and cardiovascular diseases[4, 5].
In vitro, pretreatment of mouse retinal photoreceptor 661W cells with SA 4503 dihydrochloride (10µM) for 1h before exposure to 2500 lux white light for 24h reduced light-induced cell mortality; however, this protective effect was blocked by the σ1 receptor antagonist BD-1047 (1µM)[6]. Treatment of NSC34 cells with SA 4503 dihydrochloride (10µM) for 3, 12, and 27h significantly upregulated the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) 1/2 but did not affect the protein expression of the σ1 receptor itself[7].
In vivo, subcutaneous administration of SA 4503 dihydrochloride (0.3mg/kg; once daily) for 16 days to olfactory bulbectomized (OB) rats reduced ambulation and rearing counts, significantly improving exploratory hyperactive behavior in the open-field test[8]. Oral administration of SA 4503 dihydrochloride (3 mg/kg; p.o.) to rats 24h, 5h, and 1h before testing significantly shortened the immobility time in the forced swimming test[9]. Treatment of rats with transient middle cerebral artery occlusion (tMCAO) with SA 4503 dihydrochloride (0.5mg/kg; once daily; 5 days; s.c.) starting from day 2 post-stroke, significantly increased the protein level of the microglia/macrophage activation marker IBA1 in the infarct core[4].
References:
[1] MATSUNO K, SENDA T, KOBAYASHI T, et al. SA4503, a novel cognitive enhancer, with σ1 receptor agonistic properties[J]. Behavioural brain research, 1997, 83(1-2): 221-224.
[2] MONNET F P. Sigma-1 receptor as regulator of neuronal intracellular Ca2+: clinical and therapeutic relevance[J]. Biology of the cell, 2005, 97(12): 873-883.
[3] RYSKAMP D A, KORBAN S, ZHEMKOV V, et al. Neuronal sigma-1 receptors: signaling functions and protective roles in neurodegenerative diseases[J]. Frontiers in neuroscience, 2019, 13: 474181.
[4] RUSCHER K, INACIO A R, VALIND K, et al. Effects of the sigma-1 receptor agonist 1-(3, 4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydro-chloride on inflammation after stroke[J]. 2012.
[5] LUCAS G, RYMAR V V, SADIKOT A F, et al. Further evidence for an antidepressant potential of the selective δ1 agonist SA 4503: electrophysiological, morphological and behavioural studies[J]. International journal of neuropsychopharmacology, 2008, 11(4): 485-495.
[6] SHIMAZAWA M, SUGITANI S, INOUE Y, et al. Effect of a sigma-1 receptor agonist, cutamesine dihydrochloride (SA4503), on photoreceptor cell death against light-induced damage[J]. Experimental eye research, 2015, 132: 64-72.
[7] ONO Y, TANAKA H, TAKATA M, et al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models[J]. Neuroscience letters, 2014, 559: 174-178.
[8] WANG D, NODA Y, TSUNEKAWA H, et al. Role of N-methyl-D-aspartate receptors in antidepressant-like effects of σ1 receptor agonist 1-(3, 4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA-4503) in olfactory bulbectomized rats[J]. The journal of pharmacology and experimental therapeutics, 2007, 322(3): 1305-1314.
[9] SKUZA G, ROGOZ Z. A potential antidepressant activity of SA4503, a selective σ1 receptor agonist[J]. Behavioural pharmacology, 2002, 13(7): 537-543.
SA 4503 dihydrochloride是一种具有高效选择性的σ1受体激动剂，IC50值为17nM[1]。σ1受体是一种主要存在于中枢神经系统细胞内质网中的分子伴侣蛋白，在维持细胞内稳态、调节离子通道（如钙离子、钠离子通道）和神经保护等方面起关键作用[2,3]。SA 4503 dihydrochloride通常用于各种神经（如帕金森病和抑郁症）和心血管疾病的治疗和研究[4,5]。
在体外，SA 4503 dihydrochloride（10μM）在2500 lux白光照射前1h预处理小鼠视网膜感光661W细胞24h，降低了光照射诱导的细胞死亡率，但该保护作用可被σ1受体拮抗剂BD-1047（1μM）所阻断[6]。SA 4503 dihydrochloride（10μM）处理NSC34细胞3, 12, 27h，显著上调了Akt和细胞外信号调节激酶（ERK）1/2的磷酸化水平，但未影响σ1受体本身的蛋白表达[7]。
在体内，SA 4503 dihydrochloride（0.3mg/kg; once daily）通过皮下注射处理嗅球切除（OB）大鼠16天，大鼠的行走和站立次数减少，显著改善了其在开场实验中的探索性多动行为[8]。SA 4503 dihydrochloride（3mg/kg; p.o.）在测试前24h、5h和1h各一次给药大鼠，显著缩短了大鼠在强迫游泳实验中的静止不动时间[9]。SA 4503 dihydrochloride（0.5mg/kg; once daily; s.c.）从脑卒中后第2天开始连续给药短暂性大脑中动脉闭塞（tMCAO）大鼠5天，显著提高了梗死核心区中小胶质细胞/巨噬细胞活化标志物IBA1的蛋白水平[4]。