Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. 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 the (2-aryl)-ethynyl-moiety in 8-position with smaller less lipophilic substituents produced compounds inhibiting the binding of [3H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. These compounds were able to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus and in vivo activity could be demonstrated by reversal of the LY354740-induced hypoactivity in mice after oral administration.

In a series of 1,3-dihydro-benzo[b][1,4]diazepin-2-ones the replacement of a (2-aryl)-ethynyl-moiety by smaller substitutents produced highly potent non-competitive group II mGluR antagonists. After oral administration of, for example, 7p in vivo activity by reversal of the LY354740-induced hypolocomotion in mice could be demonstrated.Figure optionsDownload as PowerPoint slide