Synthesis and characterization of 8-ethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 2. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists

A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of a cyano group by a five-membered heterocycle produced compounds inhibiting the binding of [3H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. Further modification to improve the physicochemical properties led eventually to compounds with the ability to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus.

Graphical abstractIn a series of 1,3-dihydro-benzo[b][1,4]diazepin-2-ones the replacement of a nitrile by a five-membered heterocycle produced highly potent non-competitive group II mGluR antagonists. Further modification led to compounds with the ability to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus.Figure optionsDownload full-size imageDownload as PowerPoint slide