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

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Abstract

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.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are thankful to FAPEG, FUNADESP and the workers at the Central Bioterium of the Federal University of Goiás for the research supports and contribution to this study.

Funding

The author disclosed the receipt of the Fundação Nacional de Desenvolvimento do Ensino Superior Particular (FUNADESP) scholarship in support for the research.

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Authors and Affiliations

  1. Institute of Biological Science, Federal University of Goiás, CEP 74001-970, Goiânia, GO, Brazil

    Iara Barbosa Cabral, Lorrane Kelle da Silva Moreira, Elson Alves Costa & James O. Fajemiroye

  2. Faculty of Pharmacy, Federal University of Goiás, PMB 131, CEP 74001-970, Goiânia, Brazil

    Caroline Vitória de Lima Moreira, Ana Carolina Cavalcante Rodrigues, Jhon Kennedy Alves Pereira, Luiz Carlos da Cunha, Jerônimo Raimundo de Oliveira Neto & Ricardo Menegatti

  3. Institute of Chemistry, Federal University of Goiás, Av. Esperança S/N, Campus Samambaia, Goiânia, GO, 74690-900, Brazil

    Christian Dias Gomides, Luciano M. Lião, Lucas S. Machado & Boniek G. Vaz

  4. Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, Alagoas, Maceió, 57072-900, Brazil

    Edeildo Ferreira da Silva-Júnior

  5. Research Group in Therapeutic Strategies, Federal University of Alagoas, Lourival Melo Mota Avenue, Alagoas, Maceió, 57072-900, Brazil

    Thiago Mendonça de Aquino

  6. Pharmaceutical Sciences Graduate Program (PPGCS), Federal University of Sergipe, São Cristóvão, Sergipe, 49100-001, Brazil

    Paulo Fernando da Silva Santos-Júnior

  7. Evangelical University of Goias, UniEvangélica, Av. Universitária Km 3, 5 Cidade Universitária Anápolis, Goias, GO, 75083-515, Brazil

    Osmar N. Silva & James O. Fajemiroye

  8. Department of Physiological Sciences, Institute of Biology, Federal Rural University of Rio de Janeiro, Seropédica, RJ, Brazil

    Fábio Fagundes da Rocha

Authors
  1. Iara Barbosa Cabral
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  2. Caroline Vitória de Lima Moreira
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  3. Ana Carolina Cavalcante Rodrigues
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  4. Lorrane Kelle da Silva Moreira
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  8. Lucas S. Machado
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  9. Boniek G. Vaz
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  10. Luiz Carlos da Cunha
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  11. Jerônimo Raimundo de Oliveira Neto
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  12. Edeildo Ferreira da Silva-Júnior
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  16. Fábio Fagundes da Rocha
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  17. Elson Alves Costa
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  18. Ricardo Menegatti
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  19. James O. Fajemiroye
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Contributions

Study conception and design: IBC, CVLM, ACCR, LKSM, JKAP, RM, FFR and JOF; analysis and result interpretation: CDG, LML, LSM, BGV, LCC, CVLM, ACCR, JRON, EFSJ, IBC, EAC and TMA, PFSSJ; manuscript drafting and editing: IBC, JKAP, ONS, FFR, EAC, TMA, PFSSJ, RM, JOF. All authors reviewed the results and approved the final version of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to James O. Fajemiroye.

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Ethical approval

The current research adhered to the ethical and professional conduct with all the experimental protocols approved by the Ethics Committee for the Use of Animals of the Federal University of Goiás-Brazil with the reference number 022/20.

Competing interests

The authors declare no competing interests.

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Cabral, I.B., de Lima Moreira, C.V., Rodrigues, A.C.C. et al. Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis. Naunyn-Schmiedeberg's Arch Pharmacol 396, 2957–2975 (2023). https://doi.org/10.1007/s00210-023-02502-9

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