title: Synthesis and evaluation of anticonvulsant properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and its 3-methyl-, 3-isopropyl, and 3-benzhydryl analogs.
abstract: The aim of this paper was to describe the synthesis of a library of 28 new 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents. The anticonvulsant activity was evaluated using three acute models of seizures in mice (MES-maximal electroshock, scPTZ-subcutaneous pentylenetetrazole, and 6Hz-psychomotor seizure tests). The neurotoxicity was determined by rotarod test. The most promising compound was found to be N-[{morpholin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (15), as it was active in the MES (ED50=41.0mg/kg), scPTZ (ED50=101.6kg/mg), and 6Hz (ED50=45.42mg/kg) tests. This compound displayed more beneficial protection index (PI) than antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. In vitro studies for compound 15 were conducted and provided information that its possible mechanism of action is related to blocking of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels.
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: 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* / Q000627:therapeutic use*; D008352:Mannich Bases / Q000737:chemistry*; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D008352:Mannich Bases; D011759:Pyrrolidines
keywords: Anticonvulsant activity; N-Mannich bases; Pyrrolidine-2,5-dione