Synthesis and anticonvulsant properties of new mannich bases derived from 3,3-disubstituted pyrrolidine-2,5-diones. Part IV.
A library of 21 new N-Mannich bases of 3,3-diphenyl- (5a-g), 3-methyl-3-phenyl- (6a-g), and 3-ethyl-3-methylpyrrolidine-2,5-diones (7a-g) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The acute neurological toxicity was determined applying the rotarod screen. The results in mice showed that 13 compounds were effective in the MES or/and scPTZ screen. From these, seven molecules were tested in the MES seizures after oral administration in rats. The quantitative studies showed that N-[{4-(2-hydroxyethyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6c) and N-[(4-benzylpiperidin-1-yl)-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6f) revealed higher protection in the MES and scPTZ tests than valproic acid or ethosuximide which were used as reference antiepileptic drugs. Four compounds (5c, 6c, 6e, 6f) showed high effectiveness in the 6-Hz psychomotor seizure model of partial and therapy resistant epilepsy.
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland. mfobnisk@cyf-kr.edu.pl
Jolanta
J
Obniska
Iwona
I
Chlebek
Krzysztof
K
Kamiński
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004597:Electroshock; D007274:Injections, Intraperitoneal; D008297:Male; D008352:Mannich Bases / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D013388:Succinimides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000927:Anticonvulsants; D008352:Mannich Bases; D013388:Succinimides; D010433:Pentylenetetrazole