title: Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione.
abstract: Synthesis and anticonvulsant properties of 26 new N-Mannich bases of 3-benzhydryl-(5-17) and 3-isopropyl-pyrrolidine-2,5-diones (18-30) have been described. Initial anticonvulsant screening for these compounds was evaluated in mice after intraperitoneal administration in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The acute neurological toxicity was determined by applying the rotorod test. The in vivo results in mice showed that the majority of 3-benzhydryl-pyrrolidine-2,5-dione derivatives revealed effectiveness, while 3-isopropyl-pyrrolidine-2,5-dione derivatives were practically devoid of activity. The quantitative evaluation in both tests revealed that the most active were N-[{4-(3-chlorophenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (9) with ED5 0 value =42.71 mg/kg (MES), ED5 0 value >150 mg/kg (scPTZ), and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (13) with ED5 0 value =101.46 mg/kg (MES) and ED5 0 value =72.59 mg/kg (scPTZ). These molecules showed higher potency and lower neurotoxicity than the reference antiepileptic drugs (ethosuximide and valproic acid). To explain the probable mechanism of action of selected active derivatives (9 and 13), their influence on Nav1.2 and l-type calcium channel was evaluated in vitro.
authors.affiliation: a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland and.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rybka
authors.affiliation: a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland and.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.affiliation: b Department of Pharmacodynamics , Jagiellonian University Medical College , Kraków , Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rapacz
authors.affiliation: b Department of Pharmacodynamics , Jagiellonian University Medical College , Kraków , Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland and.
authors.forename: Paweł
authors.initials: P
authors.lastname: Żmudzki
mesh_terms: D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D008352:Mannich Bases / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000927:Anticonvulsants; D008352:Mannich Bases; D011759:Pyrrolidines
keywords: Anticonvulsant activity; in vitro studies; in vivo studies; pyrrolidine-2,5-diones