Synthesis and Anticonvulsant Properties of New N-Mannich Bases Derived from 3,3-Diphenyl- and 3-Ethyl-3-methyl-pyrrolidine-2,5-diones. Part III

被引：16

作者：

Obniska, Jolanta ^{[1
]}

Chlebek, Iwona ^{[1
]}

Kaminski, Krzysztof ^{[1
]}

Karolak-Wojciechowska, Janina ^{[2
]}

机构：

[1] Jagiellonian Univ, Dept Med Chem, Coll Med, PL-30688 Krakow, Poland

[2] Tech Univ Lodz, Inst Gen & Ecol Chem, PL-90924 Lodz, Poland

来源：

ARCHIV DER PHARMAZIE | 2013年 / 346卷 / 01期

关键词：

3; 3-Disubstituted-pyrrolidine-2; 5-diones; Anticonvulsant activity; In vitro studies; In vivo studies; Mannich bases; Sodium channels; H-C INTERACTIONS; ANTIEPILEPTIC DRUGS; PACKING MOTIFS; MOLECULAR TARGETS; ANIMAL-MODELS; DERIVATIVES; MECHANISMS; CRYSTALS; SEIZURE; DESIGN;

D O I：

10.1002/ardp.201200265

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Twenty-four new N-[(4-phenylpiperazin-1-yl)-methyl] derivatives of 3,3-diphenyl- (718) and 3-ethyl-3-methyl-pyrrolidine-2,5-dione (1930) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES). In the whole series the most effective compound was N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3,3-diphenyl-pyrrolidine-2,5-dione (14) with an ED50 value of 30.3?mg/kg (p.o. rats) in the MES test. To explain the possible mechanism of action, for chosen active derivatives 7, 8, 9, 11, 14, 23, and 26, their influence on NaV1.2 sodium channel currents was evaluated in vitro. The crystallographic structures for several molecules (8, 10, and 11) were solved.

引用

页码：71 / 82

页数：12

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