Saredutant (SR 48968) is a selective (Neurokinin 2) NK2 receptor antagonist with an IC50 value of 0.13nM[1][2]. The neurokinin 2 receptor (NK2 receptor) belongs to the neurokinin receptor family and is primarily involved in various physiological processes, including smooth muscle contraction, regulation of inflammatory responses, and neurotransmission[3]. Saredutant (SR 48968) modulates these neural activities and consequently influence the occurrence and development of related diseases by antagonizing the NK2 receptor[4].
In vitro, pretreatment of CHO cells with Saredutant (SR 48968) (10-50nM) for 2 minutes before NKA stimulation (1.5-7nM) reversed the NKA-induced increases in intracellular calcium levels in a concentration dependent manner[5].
In vivo, treatment with various doses of Saredutant (SR 48968)(1, 3, and 10mg/kg in FSL, 3mg/kg in the FRL, i.p.)for 14 consecutive days increased social interaction (at 10mg/kg), reduced immobility (at 3 and 10mg/kg), and had no effect on locomotor activity in the Flinders Sensitive Line (FSL) rats, but did not affect any of these variables in the Flinders Resistant Line (FRL) rat when compared with the control rats[6]. Oral treatment Saredutant (SR 48968)(30mg/kg) demonstrated a significant reduction in stress-induced temperature, while the number of punished crossings in the four-plate was increased at all doses tested (3–30mg/kg) in the stress-induced hyperthermia (SIH) model[7].
References:
[1] Emonds-Alt, X., Advenier, C., Croci, T., Manara, L., Neliat, G., Poncelet, M., Proietto, V., Santucci, V., Soubrié, P., & Van Broeck, D. (1993). SR 48968, a neurokinin A (NK2) receptor antagonist. Regulatory peptides, 46(1-2), 31–36.
[2] Qi, H., Shah, S. K., Cascieri, M. A., Sadowski, S. J., & MaCcoss, M. (1998). L-tryptophan urea amides as NK1/NK2 dual antagonists. Bioorganic & medicinal chemistry letters, 8(16), 2259–2262.
[3] Quartara, L., Rovero, P., & Maggi, C. A. (1995). Peptide-based tachykinin NK2 receptor antagonists. Medicinal research reviews, 15(2), 139–155.
[4] Hopkins C. R. (2010). ACS chemical neuroscience molecule spotlight on Saredutant. ACS chemical neuroscience, 1(10), 653–654.
[5] Ahlstedt, I., Engberg, S., Smith, J., Perrey, C., Moody, A., Morten, J., Lagerström-Fermér, M., Drmota, T., von Mentzer, B., Påhlman, I., & Lindström, E. (2008). Occurrence and pharmacological characterization of four human tachykinin NK2 receptor variants. Biochemical pharmacology, 76(4), 476–481.
[6] Overstreet, D. H., Naimoli, V. M., & Griebel, G. (2010). Saredutant, an NK2 receptor antagonist, has both antidepressant-like effects and synergizes with desipramine in an animal model of depression. Pharmacology, biochemistry, and behavior, 96(2), 206–210.
[7] Rogacki, N., Lopez-Grancha, M., Naimoli, V., Potestio, L., Stevens, R. J., Pichat, P., Bergis, O. E., Cohen, C., Varty, G. B., & Griebel, G. (2011). The neurokinin NK2 antagonist, saredutant, ameliorates stress-induced conditions without impairing cognition. Pharmacology, biochemistry, and behavior, 98(3), 405–411.
Saredutant (SR 48968) 是一种选择性（Neurokinin 2） NK2受体拮抗剂，IC50值为0.13nM[1][2]。神经激肽2受体（NK2受体）属于神经激肽受体家族，主要参与各种生理过程，包括平滑肌收缩、炎症反应调节和神经传递[3]。Saredutant （SR 48968）通过拮抗NK2受体调节这些神经活动，从而影响相关疾病的发生和发展[4]。
在体外，在NKA刺激（1.5-7nM）之前，用Saredutant （SR 48968）（10-50nM）预处理CHO细胞2分钟，Saredutant （SR 48968）以浓度依赖的方式逆转了NKA诱导的细胞内钙水平的增加[5]。
体内实验中，Saredutant（SR 48968）以不同剂量（在Flinders敏感系大鼠中为1、3和10mg/kg，腹腔注射；在Flinders抵抗系大鼠中为3mg/kg，腹腔注射）连续给药14天，结果显示：在Flinders敏感系（FSL）大鼠中，10mg/kg Saredutant（SR 48968）增加了社交互动，3和10mg/kg剂量减少了不动时间，但对自主活动没有影响；在Flinders抵抗系（FRL）大鼠中，Saredutant（SR 48968）对上述任何变量均无影响[6]。在应激诱导的高热（SIH）模型中，口服Saredutant（SR 48968）（30mg/kg）显著降低了应激诱导的体温升高，同时在所有测试剂量（3–30mg/kg）下，四板实验中的惩罚性穿越次数增加[7]。