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Design, Docking Simulations, Synthesis, and in vitro and in vivo Behavioral Assessment of m ‐Aminobenzoic Acid Analogues as GABA‐AT Inhibitors
Author(s) -
AltamiranoEspino José A.,
CórdovaMoreno Rebeca,
AndradeJorge Erik,
MartínezArchundia Marlet,
GarcíaMachorro Jazmín,
TrujilloFerrara José G.
Publication year - 2021
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202102643
Subject(s) - vigabatrin , picrotoxin , in vivo , aminobutyric acid , gabaergic , chemistry , gamma aminobutyric acid , pharmacology , anticonvulsant , docking (animal) , in vitro , stereochemistry , gabaa receptor , biochemistry , epilepsy , biology , receptor , neuroscience , medicine , microbiology and biotechnology , nursing
γ‐Aminobutyric acid (GABA) is an inhibitory neurotransmitter whose deficiency is related to affections involving overexcited neurons (e. g., anxiety and epilepsy); rise of GABA levels by inhibition of GABA‐aminotransferase (GABA‐AT) is a treatment option. The aim of this contribution was to assess a series of m ‐aminobenzoic acid derivatives (analogous to GABA) as GABA‐AT inhibitors. Chosen compounds from docking simulations, were synthesized in good yields by green chemistry, tested in vitro for inhibition of GABA‐AT and assayed for protection against pentylenetetrazole (PTZ) induced seizures, and ability to counter picrotoxin (PTX) induced anxiety. These compounds had a lower binding energy (higher affinity) than GABA and GABA‐AT inhibitor vigabatrin (VGB) at the model active site. DABA_2 a (3,5‐dimaleamilbenzoic acid) had excellent attributes in silico (ΔG=−9.00 kcal/mol vs −5.33 kcal/mol of VGB), good competitive inhibition of GABA‐AT in vitro (K I =3.6×10 −6 M, ΔG=−7.42 kcal/mol) and a low acute toxicity (≥1,000 mg/kg) with good protection against PTZ and PTX (100 mg/kg), leading to stablish the good modulation of GABAergic transmission in vivo .