Synthesis and anticonvulsant activity of novel and potent 2,3-benzodiazepine AMPA/kainate receptor antagonists

We have previously shown that 1-aryl-3,5-dihydro-7,8-methylenedioxy-4H-2,3- benzodiazepin-4-ones (3) possess marked anticonvulsant properties and antag onize seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) acid( AMPA) in analogy to the structurally related 1-(4-aminophenyl)-4-methyl-7,8 -methylenedioxy-5H-2,3-benzodiazepine (1, GYKI: 52466), a well-known noncom petitive AMPA/kainate receptor antagonist. We now report the synthesis of 3 -(N-alkylcarbamoyl)-1-aryl-3,5-dihydro-7,8-methylenedioxy-4H (4a-h) and 1-a ryl-3,5-dihydro-7,8-methylenedioxy-4H (5a-c). The activity of all compounds , intraperitoneally (ip) injected, was evaluated against audiogenic seizure s in DBA/2 mice and against seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in Swiss mice. Some of the new compounds 4 and 5 showed remarkable anticonvulsant activity, and their toxicity, as eviden ced by the rotarod test, is lower than that of 1. The time course of antico nvulsant activity of derivatives 4b and 5b,c was studied and compared to th at of 1 and 3b,c. Compounds 4a,b and 5a-c antagonize seizures induced by AM PA and kainate (KA) and their anticonvulsant activity is reversed by pretre atment with aniracetam. Using the patch-clamp technique, the capability of derivatives 3c, 4b, and 5c to antagonize KA-evoked currents in primary cult ures of granule neurons was tested and compared with that of the parent com pounds 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-methylcarbamoyl-7,8-m ethylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655).