Trimetozine被用于治疗精神疾病，特别是焦虑症。本研究提供了Trimetozine衍生物morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289)的药理学特性数据，该衍生物是通过将Trimetozine导向物和2,6-di-tert-butyl-hydroxytoluene进行分子杂交设计的新型抗焦虑药物。我们进行了分子动力学模拟、对接研究、受体结合实验和LQFM289在剂量范围为5-20 mg/kg的小鼠中行为和生化评估前的计算机模拟ADMET评估。LQFM289的对接与苯二氮平结合位点产生强烈相互作用，并且与受体结合数据相匹配。通过这种Trimetozine衍生物的ADMET分布预测其在口服后高肠吸收和穿过血脑屏障的通透性而不被通透性糖蛋白抑制。口服LQFM289 10 mg/kg可在开放式场和黑白箱装置中引起小鼠的抗焦虑行为，而不会引起铁丝，旋转杆和烟囱测试的运动不协调。在20 mg/kg剂量下，这种Trimetozine衍生物通过线和旋转杆的下落潜伏期降低，而通过烟囱测试攀爬时间的增加，以及在开放领域装置中穿越次数的减少，表明在最高剂量下具有镇静或运动协调障碍。盐酸氟马西尼预处理减弱LQFM289（10 mg/kg）的抗焦虑效应，表明苯二氮平结合位点的参与。LQFM289-treated小鼠的皮质酮和肿瘤坏死因子α（细胞因子）的下降表明该化合物的抗焦虑效应还涉及非苯二氮平结合位点/GABAergic分子机制。©2023年。作者独家许可Springer-Verlag GmbH Germany，Springer Nature的一部分。

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.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.