Synthesis, physicochemical properties, anticonvulsant activities, and GABA-ergic and voltage-sensitive calcium channel receptor affinities of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid part 4: Search for new anticonvulsant compounds

In a search for new anticonvulsant compounds, two series of N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (series A) and alpha-(2-ph enylethylamino)-gamma-hydroxybutyric acid (series B), were investigated in maximal electroshock (MES), subcutaneous metrazole, and rotorod toxicity as says. The most,potent anticonvulsant compounds were alpha-(benzylamino)-gam ma-hydroxybutyric acid N-benzylamide (3) and N-(2-chlorobenzyl-amide (4) wi th median effective (ED50) doses 63.0 mg/kg and , respectively. alpha-(4-Ph enylpiperazinyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)amide (17) and alpha-(benzylpiperaz-inyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)ami de (18) were also tested for their ability to potentiate [H-3] -muscimol bi nding and Ifo inhibit [S-35]-TBPS binding (as indices of GABA-A receptor po tentiation). Amide 17 exhibited activity at the GABA-A complex which may be the mechanism by which the anticonvulsant effect of this compound is media ted. The N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (3 -9) were also evaluated for their ability to displace [H-3] nitrendipine fr om voltage-sensitive calcium channel (VSCC) receptors isolated from rat cor tex.