Synthesis, physicochemical properties, anticonvulsant activities and voltage-sensitive calcium channels affinity of N-substituted amides of alpha-(4-phenylpiperazino)-GABA - Part 3: Search for new anticonvulsant compounds

This paper describes the synthesis and preliminary anticonvulsant evaluatio n of some GABA analogues i.e. derivatives of 2-(4-phenylpiperazino)- or 2-( 4-benzylpiperidino)-GABA (5, 6), N-substituted amides of 2-(4-phenylpiperaz ino)-4-phthalimidobutyric acid and N-substituted amides of 2-(4-phenylpiper azino)-GABA. N-Substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobu tyric acid (7-11) were prepared by condensation of the acid with the corres ponding derivatives of benzylamine in the presence of different coupling re agents (2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and carbonyldiimidazol e (CDI)). N-Substituted benzylamides of 2-(4-phenylpiperazino)-4-aminobutyr ic acid (12-14) were prepared by hydrazinolysis of amides 9-11. Anticonvuls ant activities were determined in mice (for all compounds) and in rats usin g the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The amides (12-14) showed protection against MES and/or scMet seizures in mice. N-(4-Methoxybenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide ( 13) was the most effective and displayed anticonvulsant activity in both te sts at doses of 100-300 mg/kg in mice and at 30 mg/kg in the MES screen in rats. The active compounds (12-14) were tested for their ability to displac e [H-3]nitrendipine binding sites (voltage-sensitive calcium channel recept ors) from rat cortex. Amide 13 was the most active both in pharmacological and biochemical tests. These preliminary results suggest that the anticonvu lsant activity of compounds 12-14 may be related to their influence on volt age-sensitive calcium channel receptors.