Docking and pharmacodynamic studies on hGAT1 inhibition activity in the presence of selected neuronal and astrocytic inhibitors

Authors
Nowaczyk A, Fija_kowski _, Zar_ba P, Sa_at K

Lab
Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30 - 688, Krakow, Poland

Journal
Journal of Molecular Graphics and Modelling

Abstract
Inhibition of 4-aminobutanoic acid (GABA) uptake is a strategy for enhancing GABA transmission. The utility of this approach is demonstrated by the successful development of such agents for the treatment of epilepsy and pain. Existing reports on acute brain slice preparations indicate the intersecting of complementary channels and receptors sets between astrocytes and neurons cells. Thorough analysis of astroglial cells by means of molecular and functional studies demonstrated their active modulatory role in intercellular communication. The chemical interactions between sixteen GABA analogues and isoform of hGAT1 is outlined in the light of molecular docking results. In the in vivo part antinociceptive properties of racemic nipecotic acid, its R and S enantiomers and isonipecotic acid, each administered intraperitoneally at 3 fixed doses (10, 30 and 100_mg/kg), were assessed in a thermally-induced acute pain model i.e. the mouse hot plate test. Docking analyses provided complex binding energies, specific h-bond components, and h-bond properties, such as energies, distances and angles. In vivo tests revealed statistically significant antinociceptive properties of isonipecotic acid (10 and 30_mg/kg), R-nipecotic acid (30 and 100_mg/kg) and S-nipecotic acid (100_mg/kg) in mice. The docking data endorse the hypothesis of correlation between the strength of their chemical interactions with hGAT1 and analgesic action of studied compounds.

BIOSEB Instruments Used:
Cold Hot Plate Test (BIO-CHP)