Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2023-11, Vol.396 (11), p.2957-2975
• Main Authors: Cabral, Iara Barbosa, de Lima Moreira, Caroline Vitória, Rodrigues, Ana Carolina Cavalcante, da Silva Moreira, Lorrane Kelle, Pereira, Jhon Kennedy Alves, Gomides, Christian Dias, Lião, Luciano M., Machado, Lucas S., Vaz, Boniek G., da Cunha, Luiz Carlos, de Oliveira Neto, Jerônimo Raimundo, da Silva-Júnior, Edeildo Ferreira, de Aquino, Thiago Mendonça, da Silva Santos-Júnior, Paulo Fernando, Silva, Osmar N., da Rocha, Fábio Fagundes, Costa, Elson Alves, Menegatti, Ricardo, Fajemiroye, James O.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Anti-Anxiety Agents - therapeutic use; Anxiety; Anxiety - drug therapy; Anxiolytics; Behavior, Animal; Benzodiazepines; Benzodiazepines - pharmacology; Binding sites; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Corticosterone; Flumazenil; Hybridization; Hypnotics and Sedatives - pharmacology; Intestinal absorption; Latency; Membrane permeability; Mice; Molecular dynamics; Morpholines - pharmacology; Neurosciences; Oral administration; Permeability; Pharmacology/Toxicology; γ-Aminobutyric acid
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-023-02502-9

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.