title: Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione.
abstract: The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland. a.rapacz@uj.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
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, Cracow, 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, 30-688, Cracow, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Powroźnik
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D005557:Formaldehyde; D006358:Hot Temperature; D008297:Male; D008352:Mannich Bases / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009152:Mutagenicity Tests; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010862:Pilocarpine; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D015222:Sodium Channels / Q000378:metabolism; D013388:Succinimides / Q000494:pharmacology / Q000627:therapeutic use*; D014733:Vibrio / Q000187:drug effects / Q000235:genetics
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D020746:Calcium Channels, L-Type; D008352:Mannich Bases; D015222:Sodium Channels; D013388:Succinimides; D010862:Pilocarpine; D005557:Formaldehyde
keywords: Anticonvulsant; Antinociceptive; Ion channels binding; Lacosamide; Mutagenicity and antimutagenicity studies; Pyrrolidine-2,5-dione