Synthesis and anticonvulsant activity of new 2,3-benzodiazepines as AMPA receptor antagonists.
Novel 1-aryl-3,5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepine-4-ones (12a-j) were prepared and their anticonvulsant effects were evaluated by using various models of experimental epilepsy. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. Some of these compounds possess marked anticonvulsant properties in all tests employed. Compounds 12 antagonise seizures induced by 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 non-competitive AMPA-receptor antagonist. On the other hand, these novel 2,3-benzodiazepines exhibit anticonvulsant properties that are not affected by flumazenil, but are reversed by aniracetam. In addition, when compared to model compound 1, compounds 12 show a longer-lasting anticonvulsant activity and a lower toxicity. A structure-activity relationship study carried out on compounds 12 as well as analogous 7,8-dimethoxy derivatives 2 offers an approach for designing more potent agents.
De Sarro
A
A
Istituto di Farmacologia, Facoltà di Medicina, Università di Messina, Italy.
De Sarro
G
G
Gitto
R
R
Grasso
S
S
Micale
N
N
Zappalà
M
M
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D018091:Receptors, AMPA; D001569:Benzodiazepines