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: B Malawska, L Antkiewicz-Michaluk
• Journal: Die Pharmazie (Pharmazie) Vol. 54 Issue 4 Pg. 239-43 (Apr 1999) ISSN: 0031-7144 [Print] Germany
• PMID: 10234733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminobutyrates
• Anticonvulsants
• Calcium Channel Blockers
• Calcium Channels
• N-(4-fluorobenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide
• N-(4-methoxybenzyl)-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide
• N-benzyl-2-(4-phenylpiperazin-1-yl)-4-aminobutyric amide
• Piperazines
• Nitrendipine

Topics

• Aminobutyrates (chemical synthesis, pharmacology)
• Animals
• Anticonvulsants (chemical synthesis, pharmacology)
• Binding, Competitive
• Calcium Channel Blockers (metabolism)
• Calcium Channels (drug effects, metabolism)
• Cerebral Cortex (drug effects, metabolism)
• In Vitro Techniques
• Ion Channel Gating
• Mice
• Nitrendipine (metabolism)
• Piperazines (chemical synthesis, pharmacology)
• Radioligand Assay
• Rats