3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones: a new class of AMPA receptor antagonists.
Synthesis and evaluation of anticonvulsant activity of a series of 2,3-benzodiazepin-4-ones (2) chemically related to 1-(4'-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant properties acting as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. In an attempt to better define the structure-activity relationships (SAR) and to obtain more potent and selective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2, 3-benzodiazepine-4-thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the audiogenic seizures test with DBA/2 mice and against the maximal electroshock- and pentylenetetrazole-induced seizures in Swiss mice. New derivatives 3 showed higher potency, less toxicity and longer-lasting anticonvulsant action than those of the parent compounds 2 in all tests employed. Analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced seizures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involvement of AMPA receptors. Electrophysiological data indicate a noncompetitive blocking mechanism at the AMPA receptor sites for 3i, the most active of the series and over 5-fold more potent than 1.
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy. chimirri@pharma.unime.it
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A
Chimirri
G
G
De Sarro
A
A
De Sarro
R
R
Gitto
S
S
Quartarone
M
M
Zappalà
A
A
Constanti
V
V
Libri
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology; D003292:Convulsants / Q000633:toxicity; D004597:Electroshock; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D009833:Olfactory Pathways / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000633:toxicity; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
C114184:1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2m3-benzodiazepine-4-thione; D000927:Anticonvulsants; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D018091:Receptors, AMPA; D013871:Thiones; D001569:Benzodiazepines; C036466:aniracetam; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D010433:Pentylenetetrazole