title: Design, synthesis, and anticonvulsant activity of new N-Mannich bases derived from spirosuccinimides and spirohydantoins.
abstract: The synthesis and anticonvulsant properties of new N-Mannich bases of [7,8-f]benzo-2-aza-spiro[4.5]decane-1,3-diones (5a-h) and [7,8-f]benzo-1,3-diaza-spiro[4.5]decane-2,4-diones (7a-h) were described. Initial anticonvulsant screening was performed using intraperitoneal (ip) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the rotarod test. The majority of compounds were effective in the MES or/and scPTZ screen. The quantitative studies showed that several molecules were more potent than phenytoin, used as reference drug. Selected derivatives were screened in the 6-Hz test and also assessed for potential activity against nerve agents using the Pilocarpine Induced Status Prevention model. To explain the possible mechanism of anticonvulsant action, for chosen active derivatives, their influence on voltage-dependent Na(+) channel were tested in vitro.
authors.affiliation: Department of Medicinal Chemistry, Jagiellonian University, Medical College, Kraków, Poland. mfobnisk@cyf-kr.edu.pl
authors.forename: Jolanta
authors.initials: J
authors.lastname: Obniska
authors.forename: Hanna
authors.initials: H
authors.lastname: Byrtus
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamiński
authors.forename: Maciej
authors.initials: M
authors.lastname: Pawłowski
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Szczesio
authors.forename: Janina
authors.initials: J
authors.lastname: Karolak-Wojciechowska
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D004597:Electroshock; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D008352:Mannich Bases / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D051379:Mice; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D015222:Sodium Channels / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry; D013388:Succinimides / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000927:Anticonvulsants; D006827:Hydantoins; D008352:Mannich Bases; D015222:Sodium Channels; D013141:Spiro Compounds; D013388:Succinimides; C032620:succinimide; D010433:Pentylenetetrazole