Synthesis, physicochemical and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)alkyl]-3-phenyl- and 3-(3-methyl-phenyl)-pyrrolidine-2,5-diones.

The series of N-((4-arylpiperazin-1-yl)-alkyl)-3-phenyl- and 3-(3-methylphenyl)-pyrrolidine-2,5- diones (VIII-XXV) were synthesized and evaluated for anticonvulsant and neurotoxic properties. Initial anti- convulsant screening was performed in mice, using intraperitoneal (ip) maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole-induced (scPTZ) seizure threshold tests. The neurotoxicity was determined applying the rotorod screen. Compounds VIII-XXV revealed protection only in the electrically induced seizures or were inactive. The most active were Mannich bases of 3-(3-methylphenyl)-pyrrolidine-2,5- dione with electron-withdrawing substituents at position-3 of 4-arylpiperazine fragment (XVII, XVIII), as well as compounds with ethylene or propylene spacer between imide and 4-arylpiperazine nitrogen atoms (XX- XXII, XXV). All these compounds showed anti-MES protection in mice at doses of 100 mg/kg. Additionally, when given orally, compound XVIII was also active in rats MES screen at a dose of 30 mg/kg.