Brexpiprazole, an oral atypical antipsychotic agent, is a potent partial agonist of 5-HT1A (Ki=0.12nM) and dopamine D2L (Ki=0.3nM) receptors, and an antagonist of 5-HT2A receptor (Ki=0.47nM) [1]. Brexpiprazole enhances nerve growth by antagonizing 5-HT2A receptors and through IP3 receptor-mediated Ca2+ signaling, thereby promoting nerve growth induced by nerve growth factor (NGF)[2]. Brexpiprazole has been widely used to alleviate the positive and cognitive symptoms of schizophrenia, reduce the severity of aggressive behavior, and improve symptoms and achieve functional remission [3].
In vitro, Brexpiprazole treatment for 24 hours significantly inhibited the viability of HCT116, SW620 and NCM460 cells, with IC50 values of 27.39, 32.33 and 142.5μM, respectively[4]. Treatment with 300nM Brexpiprazole for 14 days reduced the protein expression of 5-HT1A and 5-HT7 receptors as well as the phosphorylation level of AMPK in the plasma membrane components of primary cortical astrocytes, and increased the level of connexin 43[5].
In vivo, Brexpiprazole treatment via daily intragastric administration at a dose of 5mg/kg for 17 days significantly inhibited tumor growth in a HCT116 xenograft mouse model and reduced the expression of phosphorylated AKT, P85, P38, ERK1/2 and RAF in the tumor tissues[6]. When administered orally at a dose of 0.5mg/kg/day for 28 consecutive days, Brexpiprazole caused metabolic disorders in glucose and lipid metabolism in rats, resulting in increased body weight, elevated levels of lipids and blood glucose, accompanied by hormonal imbalances (insulin, glucagon, GLP-1)[7]. For 8 consecutive weeks, a daily oral dose of 5mg/kg of Brexpiprazole was administered to the colorectal cancer mouse model, resulting in a significant reduction in the number of metastatic foci in the lung tissue of the mice[8].
References:
[1] Ishima T, Futamura T, Ohgi Y, et al. Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin–dopamine activity modulator: A role for serotonin 5-HT1A and 5-HT2A receptors[J]. European Neuropsychopharmacology, 2015, 25(4): 505-511.
[2] Das S, Barnwal P, Winston A B, et al. Brexpiprazole: so far so good[J]. Therapeutic advances in psychopharmacology, 2016, 6(1): 39-54.
[3] Siwek M, Wojtasik-Bakalarz K, Krupa A J, et al. Brexpiprazole—pharmacologic properties and use in schizophrenia and mood disorders[J]. Brain Sciences, 2023, 13(3): 397.
[4] Li T, Liu X, Long X, et al. Brexpiprazole suppresses cell proliferation and de novo lipogenesis through AMPK/SREBP1 pathway in colorectal cancer[J]. Environmental Toxicology, 2023, 38(10): 2352-2360.
[5] Fukuyama K, Motomura E, Okada M. Brexpiprazole reduces 5-HT7 receptor function on astroglial transmission systems[J]. International Journal of Molecular Sciences, 2022, 23(12): 6571.
[6] Long X, Liu X, Xia W, et al. Brexpiprazole prevents the Malignant progression of human colorectal cancer cells and increases its sensitivity to egfr inhibition[J]. Frontiers in Bioscience-Landmark, 2024, 29(5): 174.
[7] Li D, Yue Q, Liu L, et al. Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats[J]. Acta Pharmacologica Sinica, 2021, 42(8): 1267-1279.
[8] Liu X, He J, Ma A, et al. Brexpiprazole inhibits EMT and migration of colorectal cancer cells by downregulating the SREBP1/SNAI1 signaling pathway[J]. Frontiers in Oncology, 2026, 15: 1734678.
Brexpiprazole是一种口服非典型抗精神病药物，是5-HT1A（Ki=0.12nM）和dopamine D2L（Ki=0.3nM）受体的强效部分激动剂，以及5-HT2A受体（Ki=0.47nM）的拮抗剂[1]。Brexpiprazole通过拮抗5-HT2A受体以及通过IP3受体介导的Ca2+信号通路来增强神经生长，从而促进神经生长因子诱导的神经生长[2]。Brexpiprazole已被广泛用于缓解精神分裂症的阳性和认知症状，降低攻击行为的严重程度，并改善症状以实现功能缓解[3]。
在体外，Brexpiprazole处理24小时显著抑制了HCT116、SW620和NCM460细胞的活力，IC50值分别为27.39、32.33和142.5μM[5]。300nM的Brexpiprazole处理原代皮层星形胶质细胞14天，降低了质膜组分中5-HT1A和5-HT7受体的蛋白表达以及AMPK的磷酸化水平，并增加了connexin 43的水平[6]。
在体内，每日灌胃5mg/kg剂量的Brexpiprazole，连续17天，显著抑制了HCT116异种移植小鼠模型中的肿瘤生长，并降低了肿瘤组织中磷酸化AKT、P85、P38、ERK1/2和RAF的表达[6]。连续28天每日口服0.5mg/kg剂量的Brexpiprazole，导致大鼠葡萄糖和脂质代谢紊乱，表现为体重增加、血脂和血糖水平升高，并伴有激素失衡（胰岛素、胰高血糖素、GLP-1）[7]。连续8周每日口服5mg/kg剂量的Brexpiprazole给药结直肠癌小鼠模型，导致小鼠肺组织中转移灶数量显著减少[8]。