SYNTHESIS OF -1-PHENYL-3,5-DIHYDRO-4H-2,3-BENZODIAZEPINE-4-ONES AS NOVEL AND POTENT NONCOMPETITIVE AMPA RECEPTOR ANTAGONISTS

A group of )-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones was synt hesized and assayed for antagonism of rat brain a-amino-3-hydroxy-5-me thylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus o ocytes. The benzodiazepinones inhibited AMPA-activated membrane curren t responses in a manner consistent with noncompetitive, allosteric inh ibition of the receptor-channel complex. The most potent compound in t he series was ylenedioxy)-3,5-dihydro-4H-2,3-benzodiazepin-4-one (6), which had an IC50 of 2.7 mu M. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 mu M. Compound 6 also had potent ant iconvulsant 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 mu M) and weak anticonvulsant (ED50 > 10 mg/kg iv). The benzodiazepinones descr ibed herein are potent noncompetitive AMPA receptor antagonists that c ould have therapeutic potential as anticonvulsants and neuroprotectant s.