Trimetozine is used to be indicated for the treatment of mental illnesses, particularly anxiety. The present study provides data on the pharmacological profile of trimetozine derivative morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289) which was designed from molecular hybridization of trimetozine lead compound and 2,6-di-tert-butyl-hydroxytoluene to develop new anxiolytic drugs. Here, we conduct molecular dynamics simulations, docking studies, receptor binding assays, and in silico ADMET profiling of LQFM289 before its behavioral and biochemical assessment in mice within the dose range of 5–20 mg/kg. The docking of LQFM289 showed strong interactions with the benzodiazepine binding sites and matched well with receptor binding data. With the ADMET profile of this trimetozine derivative that predicts a high intestinal absorption and permeability to blood–brain barrier without being inhibited by the permeability glycoprotein, the oral administration of LQFM289 10 mg/kg consistently induced anxiolytic-like behavior of the mice exposed to the open field and light–dark box apparatus without eliciting motor incoordination in the wire, rotarod, and chimney tests. A decrease in the wire and rotarod´s fall latency coupled with an increase in the chimney test´s climbing time and a decrease in the number of crossings in the open field apparatus at the dose of 20 mg/kg of this trimetozine derivative suggest sedative or motor coordination impairment at this highest dose. The attenuation of the anxiolytic-like effects of LQFM289 (10 mg/kg) by flumazenil pretreatment implicates the participation of benzodiazepine binding sites. The lowering of corticosterone and tumor necrosis factor alpha (cytokine) in LQFM289-treated mice at a single oral (acute) dose of 10 mg/kg suggests that the anxiolytic-like effect of this compound also involves the recruitment of non-benzodiazepine binding sites/GABAergic molecular machinery.

曲美嗪用于治疗精神疾病，特别是焦虑症。本研究提供了曲美嗪衍生物吗啉（3,5-二叔丁基-4-羟基苯基）甲酮（ LQFM289 ）的药理学特征数据，该衍生物是通过曲美嗪先导化合物和 2,6-二叔丁基的分子杂交而设计的。 -丁基羟基甲苯开发新的抗焦虑药物。在这里，我们对LQFM289进行分子动力学模拟、对接研究、受体结合测定和计算机 ADMET 分析，然后在 5-20 mg/kg 剂量范围内对小鼠进行行为和生化评估。 LQFM289的对接显示出与苯二氮卓结合位点的强烈相互作用，并且与受体结合数据很好地匹配。这种曲美嗪衍生物的 ADMET 谱预测其具有高肠道吸收性和对血脑屏障的渗透性，且不受渗透性糖蛋白的抑制，口服LQFM289 10 mg/kg 持续诱导暴露于曲美嗪衍生物的小鼠的抗焦虑样行为。开放场和明暗箱装置，不会在电线、旋转杆和烟囱测试中引起运动不协调。在剂量为 20 mg/kg 的该曲美嗪衍生物时，钢丝和旋转杆的坠落潜伏期减少，加上烟囱测试攀爬时间的增加以及旷场装置中交叉次数的减少，表明具有镇静作用或在最高剂量下出现运动协调障碍。氟马西尼预处理对LQFM289 (10 mg/kg) 的抗焦虑样作用的减弱表明苯二氮卓结合位点的参与。 单次口服（急性）剂量 10 mg/kg 的LQFM289治疗小鼠体内皮质酮和肿瘤坏死因子 α（细胞因子）的降低表明该化合物的抗焦虑样作用还涉及非苯二氮卓类结合位点的募集/GABA能分子机械。