Evaluation of anxiolytic-like, anticonvulsant, antidepressant-like and antinociceptive properties of new 2-substituted 4-hydroxybutanamides with affinity for GABA transporters in mice.

PURPOSE: The inhibition of plasma membrane GABA transporters (GATs) is responsible for anxiolytic-like, anticonvulsant, antinociceptive and antidepressant-like effects in mice. It also influences animals' motor coordination and their sensitivity to ethanol. The aim of this study was to assess the pharmacological activity of two novel 2-substituted 4-hydroxybutanamides (BM 130 and BM 131) in some screening models. An attempt has been made to establish the relationship between the inhibition of GAT subtype and the observed in vivo activity. METHODS: The affinity for GAT subtypes was evaluated by means of [(3)H]GABA uptake assay. It indicated that BM 130 inhibited GAT1 and GAT2, whereas BM 131 inhibited GAT1 and GAT3. In mice anxiolytic-like, antidepressant-like, anticonvulsant and antinociceptive properties of the test compounds were assessed. Their influence on motor coordination, locomotor activity and the ability to potentiate effects of subnarcotic doses of ethanol was also tested. RESULTS: Both compounds administered intraperitoneally exerted a significant anxiolytic-like effect in the four plate test with ED50 values 3.4 and 7.9 mg/kg, respectively. At 30 mg/kg they reduced duration of immobility in the forced swim test for 33% and 19%, respectively. They had no effect on electroconvulsive threshold or pain reactivity in the hot plate assay but they were antinociceptive in the acetic acid-induced writhing test (ED50 values were 12.7 and 18.6 mg/kg, respectively) and in both phases of the formalin test (ED50 values in the first phase were 10.2 and 2.1 mg/kg for BM 130 and BM 131, respectively). No motor adverse effects were observed in mice pretreated with the test compounds in the rotarod or chimney tests but BM 131 caused a transient but statistically significant decrease of animals' locomotor activity. CONCLUSIONS: In mice BM 130 and BM 131 have anxiolytic-like, antidepressant-like and antinociceptive properties which can be attributed to their affinity for not only mGAT1 but also mGAT2-4.

Synthesis and biological evaluation of new derivatives of 2-substituted 4-hydroxybutanamides as GABA uptake inhibitors.

This study presents the synthesis of novel substituted 4-hydroxybutanamides and their influence on the activity of murine GABA transport proteins GAT1-GAT4. The active compounds, derivatives of N-arylalkyl-2-(4-diphenylmethylpiperazin-1-yl)-4-hydroxybutyramide, are characterized by pIC(50) values in range of 3.92-5.06 and by slight subtype-selectivity. Among them N-4-chlorobenzylamide was the most potent GAT inhibitor (mGAT3), while N-benzylamide was the most active in GAT1-binding assay (pK(i) = 4.96). The results pointed out that benzhydryl and benzylamide moieties are crucial for the activity of this class of compounds as murine GAT inhibitors.

Design, synthesis and pharmacological evaluation of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid with potential GABA-ergic activity. Part 6. Search for new anticonvulsant compounds.

In the recent study we have extended our investigations to the new anticonvulsant derivatives of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid (GHB). Among the obtained compounds N-benzylamide of alpha-(1,2,3,4-tetrahydroisoquinoline)-GHB (9) has demonstrated activity against maximal electroshock (MES) induced seizures in mice (at 100 mg/kg ip) and in rats (at 30 mg/kg, po dose). Lactone 8 and amide 9 have possessed a weak effect on [3H]-muscimol binding. Molecular modeling studies have revealed that anticonvulsant activity of the alpha-substituted amides of GHB might partially be explained by the orientation of the terminal benzylamide fragment.