Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists.
A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2, 3-benzodiazepin-4-one (6), which had an IC50 of 2.7 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.
Wang
Y
Y
CoCensys, Inc., 201 Technology Drive, Irvine, California 92618, USA.
Konkoy
C S
CS
Ilyin
V I
VI
Vanover
K E
KE
Carter
R B
RB
Weber
E
E
Keana
J F
JF
Woodward
R M
RM
Cai
S X
SX
D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012640:Seizures / Q000517:prevention & control; D014982:Xenopus laevis
C113171:1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihdro-4H-2,3-benzodiazepin-4-one; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001381:Azepines; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines