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.