title: Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from 3-(1-phenylethyl)- and 3-benzyl-pyrrolidine-2,5-dione.
abstract: Two series of new derivatives of pyrrolidine-2,5-dione were synthesized and evaluated for their anticonvulsant properties. Initial screening for their anticonvulsant properties was performed in mice after intraperitoneal administration, using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6-Hz seizure tests. Quantitative pharmacological research revealed that the highest level of protection was demonstrated by compound N-[{4-methylpiperazin-1-yl}-methyl]-3-(1-phenylethyl)-pyrrolidine-2,5-dione monohydrochloride (22) which was effective both in the scPTZ test (ED50=39 mg/kg) and in the 6-Hz test (ED50=36 mg/kg). This molecule showed higher potency than reference antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. With the aim of explaining the possible mechanism of action of the selected molecule, its influence on sodium and calcium channels as well as NMDA and GABAA receptors binding properties were evaluated in vitro.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: rybka.sabina@gmail.com.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rybka
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, Kraków 30-688, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, Kraków 30-688, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Furgała
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, Kraków 30-688, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Żmudzki
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D058787:GABA-A Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008352:Mannich Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D058787:GABA-A Receptor Antagonists; D008352:Mannich Bases; C000621217:N-((4-methylpiperazin-1-yl)-methyl)-3-(1-phenylethyl)-pyrrolidine-2,5-dione monohydrochloride; D010879:Piperazines; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D013388:Succinimides
keywords: Anticonvulsant activity; In vivo studies; Pyrrolidine-2,5-dione