title: 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.
abstract: This paper describes the synthesis and preliminary anticonvulsant evaluation of some GABA analogues i.e. derivatives of 2-(4-phenylpiperazino)- or 2-(4-benzylpiperidino)-GABA (5, 6), N-substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobutyric acid and N-substituted amides of 2-(4-phenylpiperazino)-GABA. N-Substituted amides of 2-(4-phenylpiperazino)-4-phthalimidobutyric acid (7-11) were prepared by condensation of the acid with the corresponding derivatives of benzylamine in the presence of different coupling reagents (2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and carbonyldiimidazole (CDI). N-Substituted benzylamides of 2-(4-phenylpiperazino)-4-aminobutyric acid (12-14) were prepared by hydrazinolysis of amides 9-11. Anticonvulsant activities were determined in mice (for all compounds) and in rats using 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 tests 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 displace [3H]nitrendipine binding sites (voltage-sensitive calcium channel receptors) from rat cortex. Amide 13 was the most active both in pharmacological and biochemical tests. These preliminary results suggest that the anticonvulsant activity of compounds 12-14 may be related to their influence on voltage-sensitive calcium channel receptors.
authors.affiliation: Department of Pharmaceutical Chemistry, Collegium Medicum of Jagiellonian University, Kraków, Poland. mfmalaws@cyf-kr.edu.pl
authors.forename: B
authors.initials: B
authors.lastname: Malawska
authors.forename: L
authors.initials: L
authors.lastname: Antkiewicz-Michaluk
mesh_terms: D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051379:Mice; D009568:Nitrendipine / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats
chemical_list: D000613:Aminobutyrates; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D015220:Calcium Channels; C119602:N-(4-fluorobenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide; C119601:N-(4-methoxybenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide; C119600:N-benzyl-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide; D010879:Piperazines; D009568:Nitrendipine