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

Autor: Cabral IB; Institute of Biological Science, Federal University of Goiás, CEP 74001-970, Goiânia, GO, Brazil., de Lima Moreira CV; Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil., Rodrigues ACC; Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil., da Silva Moreira LK; Institute of Biological Science, Federal University of Goiás, CEP 74001-970, Goiânia, GO, Brazil., Pereira JKA; Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil., Gomides CD; Institute of Chemistry, Federal University of Goiás, Av. Esperança S/N, Campus Samambaia, Goiânia, GO, 74690-900, Brazil., Lião LM; Institute of Chemistry, Federal University of Goiás, Av. Esperança S/N, Campus Samambaia, Goiânia, GO, 74690-900, Brazil., Machado LS; Institute of Chemistry, Federal University of Goiás, Av. Esperança S/N, Campus Samambaia, Goiânia, GO, 74690-900, Brazil., Vaz BG; Institute of Chemistry, Federal University of Goiás, Av. Esperança S/N, Campus Samambaia, Goiânia, GO, 74690-900, Brazil., da Cunha LC; Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil., de Oliveira Neto JR; Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil., da Silva-Júnior EF; Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, Alagoas, Maceió, 57072-900, Brazil., de Aquino TM; Research Group in Therapeutic Strategies, Federal University of Alagoas, Lourival Melo Mota Avenue, Alagoas, Maceió, 57072-900, Brazil., da Silva Santos-Júnior PF; Pharmaceutical Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, Sergipe, 49100-001, Brazil., Silva ON; Evangelical University of Goias, UniEvangélica, Av. Universitária Km 3, 5 Cidade Universitária Anápolis, Goias, GO, 75083-515, Brazil., da Rocha FF; Department of Physiological Sciences, Institute of Biology, Federal Rural University of Rio de Janeiro, Seropédica, RJ, Brazil., Costa EA; Institute of Biological Science, Federal University of Goiás, CEP 74001-970, Goiânia, GO, Brazil., Menegatti R; Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil., Fajemiroye JO; Institute of Biological Science, Federal University of Goiás, CEP 74001-970, Goiânia, GO, Brazil. jamesfajemiroye@ufg.br.; Evangelical University of Goias, UniEvangélica, Av. Universitária Km 3, 5 Cidade Universitária Anápolis, Goias, GO, 75083-515, Brazil. jamesfajemiroye@ufg.br.
Jazyk: angličtina
Zdroj: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2023 Nov; Vol. 396 (11), pp. 2957-2975. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1007/s00210-023-02502-9
Abstrakt: 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.)
Databáze: MEDLINE
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