Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives.
New cyclofunctionalized 2,3-benzodiazepines characterized by a triazolone or triazindione ring fused on the "c" edge of the heptatomic nucleus have been prepared. These compounds were evaluated as potential anticonvulsant agents, and some of them proved to be more potent noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) receptor antagonists. In particular, 8,9-dimethoxy-6-(4-bromophenyl)-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-one (5b) was almost 10-fold more active than GYKI-52466 and 3.5-fold more active than Talampanel. Furthermore, 5b potently reduced AMPA-evoked currents in electrophysiological experiments.
Gitto
Rosaria
R
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy. gittoros@pharma.unime.it
Orlando
Valérie
V
Quartarone
Silvana
S
De Sarro
Giovambattista
G
De Sarro
Angela
A
Russo
Emilio
E
Ferreri
Guido
G
Chimirri
Alba
A
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009833:Olfactory Pathways / Q000166:cytology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
C477014:8,9-dimethoxy-6-(4-bromophenyl)-11H-(1,2,4)triazolo(4,5-c)(2,3)benzodiazepin-3(2H)-one; D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D014230:Triazoles; D001569:Benzodiazepines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid