Design, synthesis, and anticonvulsant activity of new N-Mannich bases derived from spirosuccinimides and spirohydantoins.
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.
Obniska
Jolanta
J
Department of Medicinal Chemistry, Jagiellonian University, Medical College, Kraków, Poland. mfobnisk@cyf-kr.edu.pl
Byrtus
Hanna
H
Kamiński
Krzysztof
K
Pawłowski
Maciej
M
Szczesio
Małgorzata
M
Karolak-Wojciechowska
Janina
J
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
D000927:Anticonvulsants; D006827:Hydantoins; D008352:Mannich Bases; D015222:Sodium Channels; D013141:Spiro Compounds; D013388:Succinimides; C032620:succinimide; D010433:Pentylenetetrazole